|
Compound at 10E-5 M was tested in vitro for the inhibition of radioligand [3H]8-OH-DPAT binding to 5-hydroxytryptamine 1A receptor in rat hippocampal membrane
|
None
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : [[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 4
First Page : 574
Last Page : 585
Authors : Modica M, Santagati M, Russo F, Parotti L, De Gioia L, Selvaggini C, Salmona M, Mennini T.
Abstract : A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4 (1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selectivity of 24 for the 5-HT1A over the alpha 1-adrenoceptor. Compound 73, where the 2-methoxyphenyl on the N4 piperazine ring was replaced with a pyrimidine group, showed the best selectivity, with a ratio of 74, while its affinity IC50 for 5-HT1A was 6.8 nM. These results, compared to those for compounds 46 (IC50 24 nM; selectivity 2) and 49 (IC50 226 nM; selectivity 5), N3 unsubstituted analogues of derivatives 70 and 73, show the importance of an amino group in position 3 of the thienopyrimidine system for the interaction with 5-HT1A receptor binding sites, although this fragment can affect the affinity and selectivity only if linked to the (arylpiperazinyl)alkyl moiety. The better selectivity of piperidine 74 (IC50 0.8; selectivity 45) compared to the analogous piperazine 70 is also noteworthy. Twenty of the 30 molecules used for determining the binding affinity to 5-HT1A and alpha 1-adrenergic receptors were selected for QSAR analysis using a series of molecular descriptors and calculated with the TSAR software.
|
Evaluated for norepinephrine as agonist.
|
Oryctolagus cuniculus
|
3.715
nM
|
|
Journal : J. Med. Chem.
Title : Arylethanolamines derived from salicylamide with alpha- and beta-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers, and related salicylamides.
Year : 1982
Volume : 25
Issue : 6
First Page : 670
Last Page : 679
Authors : Clifton JE, Collins I, Hallett P, Hartley D, Lunts LH, Wicks PD.
Abstract : A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess beta-adrenergic blocking properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked alpha-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man, and syntheses of its four stereoisomers are described. The enantiomer 90 with the R configuration at both asymmetric centers possessed most of the beta-blocking activity but little alpha-blocking activity. That with the S configuration at the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an alpha-adrenoceptor blocking agent.
|
Inhibitory concentration required for displacement of Alpha adrenergic receptor specific ligand, 2-[ [ [(2,6-dimethoxyphenoxy) ethyl]amino]methyl]benzodioxan ([3H]WB-4101) from rat brain cerebral cortical membranes
|
None
|
90.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and adrenergic agonist properties of ring-fluorinated isoproterenols.
Year : 1982
Volume : 25
Issue : 6
First Page : 680
Last Page : 684
Authors : Kirk KL, Cantacuzène D, Collins B, Chen GT, Nimit Y, Creveling CR.
Abstract : 2-Fluoro-, 5-fluoro-, and 6-fluoroisoproterenol were synthesized by reduction of the Schiff base formed between the corresponding ring-fluorinated 3,4-bis(benzyloxy)phenethanolamine and acetone, followed by reductive debenzylation in the presence of oxalic acid to yield crystalline neutral oxalates. The apparent beta-adrenergic potencies were determined in the isolated guinea pig atria. 2-Fluoro- and 5-fluoroisoproterenol were equipotent with (+/-)-isoproterenol, while 6-fluoroisoprotenol was virtually inactive. No alpha-adrenergic agonist activity (guinea pig aorta) was shown by any of the fluoroisoproterenols. Displacement of alpha- and beta-specific radioligands from isolated membrane preparations from rat brain by the fluoroisoproterenols were in agreement with the responses of the organ preparations. Thus, the apparent fluorine-induced specificity is due to specificity at the receptor binding site. The effects of fluorine substitution are discussed with regard to the apparent negative influence of the 6-fluoro substituent on the beta-agonist properties of isoproterenol, the lack of any increase in potency due to the 2-fluoro substituent, and the possibility of fluorine-induced changes in the electron density of the aromatic ring as a possible rational for the fluorine-induced specificity of both the fluoroisoproterenols and the fluoronoirepinephrines.
|
Evaluated for norepinephrine as agonist.
|
None
|
4.786
nM
|
|
Journal : J. Med. Chem.
Title : Arylethanolamines derived from salicylamide with alpha- and beta-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers, and related salicylamides.
Year : 1982
Volume : 25
Issue : 6
First Page : 670
Last Page : 679
Authors : Clifton JE, Collins I, Hallett P, Hartley D, Lunts LH, Wicks PD.
Abstract : A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess beta-adrenergic blocking properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked alpha-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man, and syntheses of its four stereoisomers are described. The enantiomer 90 with the R configuration at both asymmetric centers possessed most of the beta-blocking activity but little alpha-blocking activity. That with the S configuration at the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an alpha-adrenoceptor blocking agent.
|
Evaluated for norepinephrine as agonist.
|
None
|
6.026
nM
|
|
Journal : J. Med. Chem.
Title : Arylethanolamines derived from salicylamide with alpha- and beta-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers, and related salicylamides.
Year : 1982
Volume : 25
Issue : 6
First Page : 670
Last Page : 679
Authors : Clifton JE, Collins I, Hallett P, Hartley D, Lunts LH, Wicks PD.
Abstract : A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess beta-adrenergic blocking properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked alpha-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man, and syntheses of its four stereoisomers are described. The enantiomer 90 with the R configuration at both asymmetric centers possessed most of the beta-blocking activity but little alpha-blocking activity. That with the S configuration at the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an alpha-adrenoceptor blocking agent.
|
In vitro postsynaptic antagonist activity against Alpha adrenergic receptor in rat anococcygeus muscle
|
None
|
19.95
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of some potential antihypertensive phthalazinyl- and quinoxalinylguanidines.
Year : 1982
Volume : 25
Issue : 7
First Page : 821
Last Page : 824
Authors : Chapleo CB, Doxey JC, Myers PL.
Abstract : A series of phthalazinyl- and quinoxalinylguanidines has been synthesized and evaluated for potential antihypertensive activity. Unsubstituted guanidines were prepared by treating the appropriate intermediate chloro compounds with guanidine free base. Substituted guanidines were prepared by treating the cyanamides 9 and 16 with the appropriate amine; with hydrazines, cyanamide 9 gave the triazoles 14 and 15. Moderate falls in blood pressure were observed with compounds 10, 11, 14, and 15. The triazole 15 caused a 25% fall in heart rate. Some of the compounds (10, 11, 13, and 18) displayed weak alpha-adrenoceptor antagonist properties in vitro, and this activity was confirmed in the pithed rat (in vivo).
|
In vitro presynaptic antagonist activity against Alpha adrenergic receptor in rat vas deferens
|
None
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of some potential antihypertensive phthalazinyl- and quinoxalinylguanidines.
Year : 1982
Volume : 25
Issue : 7
First Page : 821
Last Page : 824
Authors : Chapleo CB, Doxey JC, Myers PL.
Abstract : A series of phthalazinyl- and quinoxalinylguanidines has been synthesized and evaluated for potential antihypertensive activity. Unsubstituted guanidines were prepared by treating the appropriate intermediate chloro compounds with guanidine free base. Substituted guanidines were prepared by treating the cyanamides 9 and 16 with the appropriate amine; with hydrazines, cyanamide 9 gave the triazoles 14 and 15. Moderate falls in blood pressure were observed with compounds 10, 11, 14, and 15. The triazole 15 caused a 25% fall in heart rate. Some of the compounds (10, 11, 13, and 18) displayed weak alpha-adrenoceptor antagonist properties in vitro, and this activity was confirmed in the pithed rat (in vivo).
|
Tested for alpha adrenergic receptor agonistic activity on isolated rat vas deferens
|
None
|
138.04
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on the activity of drugs. 10. Synthesis, conformation, and pharmacological properties of 1-(2,5-dimethoxyphenyl)-2-aminoethanols and their morpholine analogues.
Year : 1983
Volume : 26
Issue : 2
First Page : 254
Last Page : 259
Authors : Epifani E, Lapucci A, Macchia B, Macchia F, Tognetti P, Breschi MC, Del Tacca M, Martinotti E, Giovannini L.
Abstract : In order to obtain a better understanding of the effects that structural parameters have on the changes of adrenergic activity when 1-aryl-2-aminoethanol derivatives are converted into their corresponding 2-arylmorpholine cyclic analogues, we synthesized 1-(2,5-dimethoxyphenyl)-2-aminoethanol derivatives 5-7 and their morpholine analogues 8-10. The preferred conformation of amino alcohols and their cyclic analogues have been determined through an H NMR and IR study. Compounds 5 and 6 showed both alpha-stimulating and alpha-blocking activity on rat vas deferens, the effect depending on the concentration employed; on the same isolated tissue, N-isopropyl derivative 7 and the morpholine analogues 8-10 exhibited only alpha-blocking activity. As for the beta-adrenergic activity, only the open-chain compound 7 possessed a moderate blocking effect on isolated guinea pig atria. The results of this work seem to indicate that the changes of pharmacological activity involved in the transformation of the adrenergic drugs into their morpholine analogues are influenced more by characteristic features of the aromatic moiety than by the ethanolamine or propanolamine structure of the drugs.
|
Displacement of [3H]clonidine from Alpha-2 adrenergic receptor of rat brain membranes
|
Rattus norvegicus
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs.
Year : 1982
Volume : 25
Issue : 12
First Page : 1389
Last Page : 1401
Authors : Timmermans PB, van Zwieten PA.
|
Antagonistic activity against Alpha-2 adrenergic receptor in the prostatic portion of the rat vas deferens
|
None
|
9.333
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for 2-substituted imidazoles as alpha 2-adrenoceptor antagonists.
Year : 1982
Volume : 25
Issue : 6
First Page : 666
Last Page : 670
Authors : Caroon JM, Clark RD, Kluge AF, Olah R, Repke DB, Unger SH, Michel AD, Whiting RL.
Abstract : Several 2-[(1,4-benzodioxan-2-yl)alkyl]imidazoles were prepared and evaluated for their blocking activity and relative selectivity on presynaptic (alpha 2) and postsynaptic (alpha 1) receptors in the isolated rat vas deferens. 1-Ethyl-2-[(1,4-benzodioxan 2-yl)methyl]imidazole (13) was the most selective alpha 2-adrenoceptor antagonist of the series and was, for practical purposes, devoid of alpha 1-adrenoceptor antagonist activity. The lipophilicity of 13 (log D = 2.31) indicated that it would have an excellent chance to enter the central nervous system. Compound 13 was selected for clinical evaluation as an antidepressant agent.
|
Antagonistic activity against presynaptic alpha-2 adrenergic receptor in isolated rat vas deferens using xylazine as agonist
|
None
|
16.6
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Antagonistic potency of compound for Alpha-2 adrenergic receptor
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Displacement of [3H]prazosin (0.3 nM) from rat Alpha-1D adrenergic receptor expressed in CHO cells
|
None
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective alpha(1) adrenoceptor antagonists.
Year : 2003
Volume : 46
Issue : 2
First Page : 265
Last Page : 283
Authors : Balle T, Perregaard J, Ramirez MT, Larsen AK, Søby KK, Liljefors T, Andersen K.
Abstract : A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.
|
Antagonistic activity against Alpha-1 adrenergic receptor in the epidermal portion of the rat vas deferens
|
None
|
11.48
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships for 2-substituted imidazoles as alpha 2-adrenoceptor antagonists.
Year : 1982
Volume : 25
Issue : 6
First Page : 666
Last Page : 670
Authors : Caroon JM, Clark RD, Kluge AF, Olah R, Repke DB, Unger SH, Michel AD, Whiting RL.
Abstract : Several 2-[(1,4-benzodioxan-2-yl)alkyl]imidazoles were prepared and evaluated for their blocking activity and relative selectivity on presynaptic (alpha 2) and postsynaptic (alpha 1) receptors in the isolated rat vas deferens. 1-Ethyl-2-[(1,4-benzodioxan 2-yl)methyl]imidazole (13) was the most selective alpha 2-adrenoceptor antagonist of the series and was, for practical purposes, devoid of alpha 1-adrenoceptor antagonist activity. The lipophilicity of 13 (log D = 2.31) indicated that it would have an excellent chance to enter the central nervous system. Compound 13 was selected for clinical evaluation as an antidepressant agent.
|
Antagonistic activity against postsynaptic Alpha-1 adrenergic receptor in isolated rat vas deferens using (-)-phenylephrine as agonist
|
None
|
9.55
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Antagonistic potency of compound for Alpha-1 adrenergic receptor
|
None
|
12.59
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Methoxamine antagonistic activity against alpha-1 adrenergic receptor in isolated, field -simulated vas deferens from rats
|
None
|
7.943
nM
|
|
Journal : J. Med. Chem.
Title : alpha-Adrenergic activities of some substituted 2-(aminomethyl)imidazolines.
Year : 1983
Volume : 26
Issue : 12
First Page : 1769
Last Page : 1772
Authors : Saari WS, Halczenko W, Randall WC, Lotti VJ.
Abstract : A series of 2-(aminomethyl)imidazolines related to the alpha-adrenergic antagonist phentolamine was prepared and evaluated for alpha-adrenergic agonist and antagonist activities in the isolated, field-stimulated rat vas deferens. Affinities for alpha-adrenergic receptors were determined by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex. This series provided a variety of alpha-adrenergic profiles, with some of the (aminomethyl)imidazolines being nonselective alpha 1- and alpha 2-adrenergic antagonists like phentolamine, while others were either nonselective alpha 1- and alpha 2-agonists or mixed alpha 1-agonists/alpha 2-antagonists.
|
Binding affinity against alpha-2 adrenergic receptor from calf cerebral cortex, using [3H]clonidine as the radioligand
|
None
|
0.93
nM
|
|
Journal : J. Med. Chem.
Title : alpha-Adrenergic activities of some substituted 2-(aminomethyl)imidazolines.
Year : 1983
Volume : 26
Issue : 12
First Page : 1769
Last Page : 1772
Authors : Saari WS, Halczenko W, Randall WC, Lotti VJ.
Abstract : A series of 2-(aminomethyl)imidazolines related to the alpha-adrenergic antagonist phentolamine was prepared and evaluated for alpha-adrenergic agonist and antagonist activities in the isolated, field-stimulated rat vas deferens. Affinities for alpha-adrenergic receptors were determined by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex. This series provided a variety of alpha-adrenergic profiles, with some of the (aminomethyl)imidazolines being nonselective alpha 1- and alpha 2-adrenergic antagonists like phentolamine, while others were either nonselective alpha 1- and alpha 2-agonists or mixed alpha 1-agonists/alpha 2-antagonists.
|
Binding affinity against alpha-2 adrenergic receptor from calf cerebral cortex, using [3H]prazosin as the radioligand
|
None
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : alpha-Adrenergic activities of some substituted 2-(aminomethyl)imidazolines.
Year : 1983
Volume : 26
Issue : 12
First Page : 1769
Last Page : 1772
Authors : Saari WS, Halczenko W, Randall WC, Lotti VJ.
Abstract : A series of 2-(aminomethyl)imidazolines related to the alpha-adrenergic antagonist phentolamine was prepared and evaluated for alpha-adrenergic agonist and antagonist activities in the isolated, field-stimulated rat vas deferens. Affinities for alpha-adrenergic receptors were determined by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex. This series provided a variety of alpha-adrenergic profiles, with some of the (aminomethyl)imidazolines being nonselective alpha 1- and alpha 2-adrenergic antagonists like phentolamine, while others were either nonselective alpha 1- and alpha 2-agonists or mixed alpha 1-agonists/alpha 2-antagonists.
|
The compound was tested for binding affinity against Alpha-2A adrenergic receptor from human clones.
|
None
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Antagonistic activity against adrenergic alpha-2 receptor in longitudinal muscle strip of the guinea pig ileum using l-norepinephrine as agonist
|
Rattus norvegicus
|
1.514
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Antagonistic activity against longitudinal muscle strip of the guinea pig ileum using xylazine as agonist
|
Cavia porcellus
|
15.49
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
In vitro for relative blocking action (pA2) of Presynaptic Alpha-2 adrenergic receptor from guinea pig ileum.
|
Cavia porcellus
|
3.162
nM
|
|
Journal : J. Med. Chem.
Title : Arylethanolamines derived from salicylamide with alpha- and beta-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers, and related salicylamides.
Year : 1982
Volume : 25
Issue : 6
First Page : 670
Last Page : 679
Authors : Clifton JE, Collins I, Hallett P, Hartley D, Lunts LH, Wicks PD.
Abstract : A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess beta-adrenergic blocking properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked alpha-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man, and syntheses of its four stereoisomers are described. The enantiomer 90 with the R configuration at both asymmetric centers possessed most of the beta-blocking activity but little alpha-blocking activity. That with the S configuration at the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an alpha-adrenoceptor blocking agent.
|
The compound was tested for the concentration to inhibit 50% of Alpha-1 adrenergic receptor isolated from rat ventricle homogenates.
|
None
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and adrenergic activity of a new series of N-aryl dicyclopropyl ketone oxime ethers: SAR and stereochemical aspects.
Year : 1998
Volume : 41
Issue : 10
First Page : 1613
Last Page : 1618
Authors : Blanc M, Tamir A, Aubriot S, Michel MC, Bouzoubaa M, Leclerc G, Demenge P.
Abstract : A novel series of 31 N-aryl dicyclopropyl ketone oxime ethers were synthesized and tested for their activity at alpha- and beta-adrenergic receptors. All of the compounds showed greater affinity for beta-than for alpha1-receptor sites. Some compounds had pure antagonist effects whereas some were partial agonists. Several compounds had an antagonist effect matching that of propranolol in in vitro (binding data and pA2 values on rat heart ventricle homogenates and guinea pig spontaneously beating right and electrically driven left atrial isolated preparations, respectively) and in in vivo tests (measurement of antagonism toward isoprenaline-induced tachycardia in anesthetized rats). Furthermore, all of the compounds showed a beta1-adrenergic selectivity (beta2-affinity > 1500 nM).
|
Binding affinity against alpha-2-adrenergic receptor using 10 nM [3H]yohimbine in human platelet membranes from three separate experiments using 10 inhibitor concentrations
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of an affinity ligand for purification of alpha 2-adrenoceptors from human platelet membranes.
Year : 1984
Volume : 27
Issue : 7
First Page : 918
Last Page : 921
Authors : DeMarinis RM, Krog AJ, Shah DH, Lafferty J, Holden KG, Hieble JP, Matthews WD, Regan JW, Lefkowitz RJ, Caron MG.
Abstract : Human platelets contain alpha 2-adrenoceptors which are negatively coupled to the enzyme adenylate cyclase. In order to better understand the interaction of this subtype of alpha receptor with this key enzyme, we have initiated a program to isolate and characterize the alpha 2-adrenoceptor. This report describes the synthesis and biological characterization of a series of molecules that were prepared as affinity ligands for this purpose. The best of these is 9-(allyloxy)-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 101253). This compound is an alpha 2-adrenoceptor antagonist, which was obtained by synthetic modification of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 86466), a novel antagonist with high affinity for the alpha 2-receptor.
|
Binding affinity against Alpha-2B adrenergic receptor from human clones.
|
Homo sapiens
|
7.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Antagonistic activity against postsynaptic alpha-1 adrenergic receptor in rabbit pulmonary artery using l-norepinephrine as agonist
|
Oryctolagus cuniculus
|
15.14
nM
|
|
Journal : J. Med. Chem.
Title : Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.
Year : 1987
Volume : 30
Issue : 8
First Page : 1355
Last Page : 1359
Authors : Vizi ES, Toth I, Somogyi GT, Szabo L, Harsing LG, Szantay C.
Abstract : The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.
|
Activity at alpha-1 adrenergic receptor in rabbit aorta rings
|
Oryctolagus cuniculus
|
15.85
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Z1046, a novel peripheral dopaminergic agent
Year : 1996
Volume : 6
Issue : 22
First Page : 2795
Last Page : 2800
Authors : Montanari S, Bertolini G, Casagrande C, Cavalleri P, Ferlenga P, Marchini F, Pradella L, Pocchiari F, Santangelo F, Semeraro C
|
Binding affinity against Alpha-2C adrenergic receptor from human clones.
|
Homo sapiens
|
8.4
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Inhibition of specific [3H]prazosin binding (0.2 nM) to rat brain membranes alpha-1 adrenergic receptor
|
Oryctolagus cuniculus
|
32.36
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
In vitro relative blocking action (pA2) of the post-synaptic alpha-1-adrenoceptor from rat and rabbit aorta.
|
None
|
3.162
nM
|
|
Journal : J. Med. Chem.
Title : Arylethanolamines derived from salicylamide with alpha- and beta-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers, and related salicylamides.
Year : 1982
Volume : 25
Issue : 6
First Page : 670
Last Page : 679
Authors : Clifton JE, Collins I, Hallett P, Hartley D, Lunts LH, Wicks PD.
Abstract : A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess beta-adrenergic blocking properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked alpha-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man, and syntheses of its four stereoisomers are described. The enantiomer 90 with the R configuration at both asymmetric centers possessed most of the beta-blocking activity but little alpha-blocking activity. That with the S configuration at the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an alpha-adrenoceptor blocking agent.
|
Displacement of [3H]prazosin (0.3 nM) from bovine Alpha-1A adrenergic receptor expressed in BHK cells
|
None
|
6.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective alpha(1) adrenoceptor antagonists.
Year : 2003
Volume : 46
Issue : 2
First Page : 265
Last Page : 283
Authors : Balle T, Perregaard J, Ramirez MT, Larsen AK, Søby KK, Liljefors T, Andersen K.
Abstract : A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.
|
In vitro for the displacement of [3H]prazosin binding to bovine Alpha-1A adrenergic receptor
|
None
|
0.7943
nM
|
|
Journal : J. Med. Chem.
Title : N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
Year : 1997
Volume : 40
Issue : 17
First Page : 2674
Last Page : 2687
Authors : Elworthy TR, Ford AP, Bantle GW, Morgans DJ, Ozer RS, Palmer WS, Repke DB, Romero M, Sandoval L, Sjogren EB, Talamás FX, Vazquez A, Wu H, Arredondo NF, Blue DR, DeSousa A, Gross LM, Kava MS, Lesnick JD, Vimont RL, Williams TJ, Zhu QM, Pfister JR, Clarke DE.
Abstract : Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
|
The compound was tested for binding affinity against alpha-2D adrenergic receptor, from rat clones.
|
Rattus norvegicus
|
4.7
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Compound was tested for the inhibition of [3H]prazosin binding Alpha-1 adrenergic receptor of crude rat brain membrane.
|
None
|
9.8
nM
|
|
Journal : J. Med. Chem.
Title : 1-(alkylamino)isochromans: hypotensives with peripheral and central activities.
Year : 1982
Volume : 25
Issue : 1
First Page : 75
Last Page : 81
Authors : McCall JM, McCall RB, TenBrink RE, Kamdar BV, Humphrey SJ, Sethy VH, Harris DW, Daenzer C.
Abstract : A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.
|
Alpha-2 adrenergic receptor pA2 value against clonidine in vitro experiment in rat vas deferens
|
None
|
4.169
nM
|
|
Journal : J. Med. Chem.
Title : alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants.
Year : 1983
Volume : 26
Issue : 6
First Page : 823
Last Page : 831
Authors : Chapleo CB, Myers PL, Butler RC, Doxey JC, Roach AG, Smith CF.
Abstract : The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of alpha 2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic alpha 2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings have been examined, as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.
|
Alpha-2 adrenergic receptor pA2 value against norepinephrine in vitro experiment in rat anococcygeus.
|
None
|
19.95
nM
|
|
Journal : J. Med. Chem.
Title : alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants.
Year : 1983
Volume : 26
Issue : 6
First Page : 823
Last Page : 831
Authors : Chapleo CB, Myers PL, Butler RC, Doxey JC, Roach AG, Smith CF.
Abstract : The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of alpha 2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic alpha 2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings have been examined, as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.
|
Alpha-1-adrenolytic activity was assessed from the ability to inhibit [3H]prazosin binding to rat cerebral cortex preparation
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.
Year : 1989
Volume : 32
Issue : 6
First Page : 1402
Last Page : 1407
Authors : Marciniak G, Delgado A, Leclerc G, Velly J, Decker N, Schwartz J.
Abstract : A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.
|
Alpha-1-adrenolytic activity was assessed in vitro from the ability to inhibit clonidine binding to rat aorta preparation
|
None
|
9.772
nM
|
|
Journal : J. Med. Chem.
Title : New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.
Year : 1989
Volume : 32
Issue : 6
First Page : 1402
Last Page : 1407
Authors : Marciniak G, Delgado A, Leclerc G, Velly J, Decker N, Schwartz J.
Abstract : A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.
|
In vitro inhibitory activity against Alpha-1 adrenergic receptor by using [3H]prazosin radioligand binding assay
|
Rattus norvegicus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)alkyl]piperazines and their analogues: influence of the stereochemistry of the tetrahydronaphthalen-1-yl nucleus on 5-HT1A receptor affinity and selectivity versus alpha1 and D2 receptors. 5.
Year : 1999
Volume : 42
Issue : 3
First Page : 490
Last Page : 496
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V.
Abstract : Some 1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperazines and their alkylamino and alkylamido analogues, previously studied as 5-HT1A ligands, were prepared in enantiomerically pure form, and their absolute configuration was determined by chemical correlation or by chiroptical properties. They were evaluated for in vitro 5-HT1A, D2, and alpha1 receptor affinity by radioligand binding assays, to study the influence of the chiral carbon atom of the tetrahydronaphthalene nucleus on the 5-HT1A affinity and selectivity. Results indicated that, as regarding the 5-HT1A receptor affinity, there was no difference in affinity between (-)- and (+)-enantiomers as well as the racemate of each compound. The stereochemistry, instead, influenced the selectivity: all (-)-enantiomers displayed affinity values higher than those of (+)-isomers at D2 receptors, and conversely, all (+)-enantiomers displayed affinity values higher than those of (-)-isomers at alpha1 receptors. As a result of this trend, it is not possible to predict the isomer with a better selectivity profile. However, compounds (S)-(+)-2, (S)-(+)-4, and (R)-(+)-6 displayed high affinity for the 5-HT1A receptor (IC50 values ranging between 7.0 and 2.3 nM) and good selectivity (>/=250-fold) versus both D2 and alpha1 receptors. Furthermore, compounds (S)-(+)-4 and (R)-(-)-4 were submitted to the [35S]GTPgammaS binding assay for a preliminary evaluation of their intrinsic activity on the 5-HT1A receptor.
|
Alpha-2 adrenergic receptor activity was assessed from the ability to inhibit [3H]yohimbine binding to rat cerebral cortex preparation
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.
Year : 1989
Volume : 32
Issue : 6
First Page : 1402
Last Page : 1407
Authors : Marciniak G, Delgado A, Leclerc G, Velly J, Decker N, Schwartz J.
Abstract : A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.
|
Concentration of compound for 50% displacement of [3H]WB-4101 from Alpha-1 adrenergic receptor of rat brain
|
None
|
5.2
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogues.
Year : 1980
Volume : 23
Issue : 8
First Page : 865
Last Page : 873
Authors : Martin AR, Paradkar VM, Peng GW, Speth RC, Yamamura HI, Horn AS.
|
In vitro inhibitory concentration against radioligand [3H]prazosin binding to alpha-1 adrenergic receptor in rat cortical membrane.
|
None
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : [[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 4
First Page : 574
Last Page : 585
Authors : Modica M, Santagati M, Russo F, Parotti L, De Gioia L, Selvaggini C, Salmona M, Mennini T.
Abstract : A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4 (1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selectivity of 24 for the 5-HT1A over the alpha 1-adrenoceptor. Compound 73, where the 2-methoxyphenyl on the N4 piperazine ring was replaced with a pyrimidine group, showed the best selectivity, with a ratio of 74, while its affinity IC50 for 5-HT1A was 6.8 nM. These results, compared to those for compounds 46 (IC50 24 nM; selectivity 2) and 49 (IC50 226 nM; selectivity 5), N3 unsubstituted analogues of derivatives 70 and 73, show the importance of an amino group in position 3 of the thienopyrimidine system for the interaction with 5-HT1A receptor binding sites, although this fragment can affect the affinity and selectivity only if linked to the (arylpiperazinyl)alkyl moiety. The better selectivity of piperidine 74 (IC50 0.8; selectivity 45) compared to the analogous piperazine 70 is also noteworthy. Twenty of the 30 molecules used for determining the binding affinity to 5-HT1A and alpha 1-adrenergic receptors were selected for QSAR analysis using a series of molecular descriptors and calculated with the TSAR software.
|
Inhibition of [3H]WB-4101 binding to alpha-1-adrenergic receptor from rat cerebral cortex membranes
|
None
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives.
Year : 1983
Volume : 26
Issue : 2
First Page : 194
Last Page : 203
Authors : Yevich JP, Temple DL, New JS, Taylor DP, Riblet LA.
Abstract : A series of analogues of buspirone was synthesized in which modifications were made in the aryl moiety, alkylene chain length, and cyclic imide portion of the molecule. These compounds were tested in vitro for their binding affinities to rat brain membrane sites labeled by either the dopamine antagonist [3H]spiperone or the alpha 1-adrenergic antagonist [3H]WB-4101. Compounds were also tested in vivo for tranquilizing properties and induction of catalepsy. Potency at the [3H]spiperone binding site was affected by alkylene chain length and imide portion composition. Nonortho substituents on the aryl moiety had little effect on [3H]spiperone binding affinity. Structure-activity relationships of ortho substituents demonstrated only modest correlations between the receptor binding data and physical parameters of the substituents. The complex nature of the drug-receptor interactions may be understood in terms of the fit of buspirone to a hypothetical model of the dopamine receptor.
|
Inhibition of specific [3H]clonidine binding (0.4 nM) to rat brain membranes Alpha-2 adrenergic receptor
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
Antagonistic activity against alpha 1A/1L receptor was assessed in a rabbit bladder neck functional assay
|
Oryctolagus cuniculus
|
6.31
nM
|
|
Journal : J. Med. Chem.
Title : N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
Year : 1997
Volume : 40
Issue : 17
First Page : 2674
Last Page : 2687
Authors : Elworthy TR, Ford AP, Bantle GW, Morgans DJ, Ozer RS, Palmer WS, Repke DB, Romero M, Sandoval L, Sjogren EB, Talamás FX, Vazquez A, Wu H, Arredondo NF, Blue DR, DeSousa A, Gross LM, Kava MS, Lesnick JD, Vimont RL, Williams TJ, Zhu QM, Pfister JR, Clarke DE.
Abstract : Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
|
Displacement of [3H]prazosin (0.5 nM) from hamster Alpha-1B adrenergic receptor expressed in rat-1 cells
|
mesocricetus auratus (golden hamster)
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective alpha(1) adrenoceptor antagonists.
Year : 2003
Volume : 46
Issue : 2
First Page : 265
Last Page : 283
Authors : Balle T, Perregaard J, Ramirez MT, Larsen AK, Søby KK, Liljefors T, Andersen K.
Abstract : A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.
|
Binding affinity towards Alpha-2 adrenergic receptor, using [3H]- atipamezole as radioligand from rat frontal cortex membranes
|
None
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of 2,3-dimethoxy-5-(fluoroalkyl)-substituted benzamides: high-affinity ligands for CNS dopamine D2 receptors.
Year : 1991
Volume : 34
Issue : 5
First Page : 1612
Last Page : 1624
Authors : Bishop JE, Mathis CA, Gerdes JM, Whitney JM, Eaton AM, Mailman RB.
Abstract : A number of 2,3-dimethoxy-5-(fluoroalkyl)-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamides (with or without a 6-hydroxy group) were synthesized and evaluated as dopamine D2 receptor ligands. The parent acids were synthesized via the Claisen rearrangement of the appropriate O-allyl ethers, which were derived from o-vanillic acid or 2,3-dimethoxysalicylic acid. A decrease in reactivity was found to be characteristic of pentasubstituted benzoates, and difficulties were encountered with the introduction of fluorine onto the ethyl side chains. The (fluoroethyl)- and (fluoropropyl)salicylamides were 5 times more potent than the corresponding benzamides in inhibiting [3H]spiperone binding to the D2 receptor. These (fluoroalkyl)salicylamides are of potential value for in vivo positron emission tomography (PET) studies upon the basis of their relatively selective, high potency binding affinity for the D2 receptor.
|
Ability to displace [3H]prazosin (0.25 nM) from whole brain of rat alpha-1 adrenergic receptor
|
None
|
90.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective alpha(1) adrenoceptor antagonists.
Year : 2003
Volume : 46
Issue : 2
First Page : 265
Last Page : 283
Authors : Balle T, Perregaard J, Ramirez MT, Larsen AK, Søby KK, Liljefors T, Andersen K.
Abstract : A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.
|
Binding affinity towards Alpha-1 adrenergic receptor from rat cortical membranes
|
None
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D(3) receptor ligands.
Year : 2002
Volume : 45
Issue : 26
First Page : 5727
Last Page : 5735
Authors : Leopoldo M, Berardi F, Colabufo NA, De Giorgio P, Lacivita E, Perrone R, Tortorella V.
Abstract : The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D(4) receptor ligand, has been modified searching for structural features that could lead to D(3) receptor affinity. Changes in the aromatic ring linked to N-1 piperazine ring led to the identification of 2-methoxyphenyl and 2,3-dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D(3) affinity (K(i) = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13 improved binding affinity for the D(3) receptor and decreased the D(4) affinity (compounds 18-26). Among these latter compounds, the N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (19) was further modified with the replacement or of the 2,3-dichlorophenyl moiety (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way, we identified several high-affinity D(3) ligands (0.13 nM < K(i)'s < 4.97 nM) endowed with high selectivity over D(2), D(4), 5-HT(1A), and alpha(1) receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (41) appear to be valuable candidates for positron emission tomography (PET) because of their affinity values, lipophilicity properties, and liability of (11)C labeling in the O-methyl position.
|
Compound was tested for the inhibition of [3H]clonidine binding Alpha-2 adrenergic receptor of crude rat brain membrane
|
None
|
9.3
nM
|
|
Journal : J. Med. Chem.
Title : 1-(alkylamino)isochromans: hypotensives with peripheral and central activities.
Year : 1982
Volume : 25
Issue : 1
First Page : 75
Last Page : 81
Authors : McCall JM, McCall RB, TenBrink RE, Kamdar BV, Humphrey SJ, Sethy VH, Harris DW, Daenzer C.
Abstract : A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.
|
Binding affinity towards alpha-1 adrenergic receptor in rat cortical membranes
|
None
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: a new class of potent and selective 5-HT(1A) receptor ligands as conformationally constrained analogues of 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-arylpiperazines.
Year : 2001
Volume : 44
Issue : 25
First Page : 4431
Last Page : 4442
Authors : Perrone R, Berardi F, Colabufo NA, Leopoldo M, Lacivita E, Tortorella V, Leonardi A, Poggesi E, Testa R.
Abstract : The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D2, and alpha1 receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K(i), nM: 5-HT1A = 0.028, D2 = 2194, alpha1 = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D2, and alpha1 receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D2 and alpha1 receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha1a, alpha1b, alpha1d receptor subtypes. They were also submitted to the [35S]GTPgammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K(i)) and in vitro activity (pD'2) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.
|
Percent inhibition of the pressor responses to 0.75 ug/kg iv norepinephrine in pentobarbital-anesthetized dogs for a dose of 1 mg/kg
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 0.75 ug/kg iv norepinephrine in pentobarbital-anesthetized dogs for a dose of 10 mg/kg
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 0.75 ug/kg iv norepinephrine in pentobarbital-anesthetized dogs for a dose of 5.0 mg/kg
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 1 ug/kg iv Epinephrine in pentobarbital-anesthetized dogs for a dose of 0.1 mg/kg
|
Canis lupus familiaris
|
41.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 1 ug/kg iv Epinephrine in pentobarbital-anesthetized dogs for a dose of 1 mg/kg
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 1 ug/kg iv Epinephrine in pentobarbital-anesthetized dogs for a dose of 10 mg/kg
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 7.5 ug/kg iv phenylephrine in pentobarbital-anesthetized dogs for a dose of 0.1 mg/kg
|
Canis lupus familiaris
|
42.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 7.5 ug/kg iv phenylephrine in pentobarbital-anesthetized dogs for a dose of 1 mg/kg
|
Canis lupus familiaris
|
86.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Percent inhibition of the pressor responses to 7.5 ug/kg iv phenylephrine in pentobarbital-anesthetized dogs for a dose of 10 mg/kg
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.
Year : 1981
Volume : 24
Issue : 11
First Page : 1320
Last Page : 1328
Authors : Caroon JM, Clark RD, Kluge AF, Nelson JT, Strosberg AM, Unger SH, Michel AD, Whiting RL.
Abstract : Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.
|
Inhibition of specific [3H]-prazosin binding (0.2 nM) to rat brain membranes alpha1 adrenoceptor.
|
None
|
39.0
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
Compound was tested for alpha-adrenoceptor blocking activity by its ability to antagonize norepinephrine contraction in the rat thoracic aorta
|
Rattus norvegicus
|
8.511
nM
|
|
Journal : J. Med. Chem.
Title : Pyrimidine derivatives. 4. Synthesis and antihypertensive activity of 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazoline derivatives.
Year : 1983
Volume : 26
Issue : 3
First Page : 411
Last Page : 416
Authors : Sekiya T, Hiranuma H, Hata S, Mizogami S, Hanazuka M, Yamada S.
Abstract : A series of 30 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazoline derivatives was prepared and tested for their ability to reduce blood pressure in conscious, spontaneously hypertensive rates (SHR). A number of these compounds, notably 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazolines 3a (R1 = H; R2 = Ph), 3j (R1 = H; R2 = 4-EtOPh), and 5a (R1 = H; R2 = 2-furyl), showed activity at oral doses of 0.3-10 mg/kg. The effects of the 4-substituents of the piperazino group on activity are discussed. Compounds 3a, 3j, and 5a were effective in renal hypertensive rats at oral doses of 3 and 10 mg/kg and showed alpha-adrenoceptor blocking effects in isolated aortas of rats. A 5-day consecutive oral administration of 3a and 3j in SHR did not lead to development of tolerance.
|
Antagonist activity against phenylephrine-induced alpha1- adrenoceptor mediated vasoconstriction in pithed normotensive rats.
|
Rattus norvegicus
|
112.2
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
Antagonist activity against B-HT 933-induced alpha-2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats
|
Rattus norvegicus
|
338.84
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.
Year : 1984
Volume : 27
Issue : 4
First Page : 495
Last Page : 503
Authors : Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA.
Abstract : Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
|
The compound was tested for affinity towards sigma-3 receptor
|
None
|
549.54
nM
|
|
Journal : J. Med. Chem.
Title : Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.
Year : 1994
Volume : 37
Issue : 24
First Page : 4109
Last Page : 4117
Authors : Myers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, Booth RG, Wyrick SD.
Abstract : Molecular modeling studies were carried out on a series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), several PAT structural analogs, and various non-PAT ligands that demonstrate a range of affinities for a novel sigma 3 receptor linked to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. In an effort to develop a ligand-binding model for the sigma 3 receptor, a pharmacophore mapping program (DISCO) was used to identify structural features that are common to ligands that exhibit moderate to high binding affinity for sigma 3 sites. DISCO then was utilized to propose a common pharmacophoric region that included one low-energy conformation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma 3 receptor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs that could potentially display high affinity and selectivity for the sigma 3 receptor. The excluded volumes which resulted from comparing molecular volumes of active and inactive compounds were visualized to examine the limits of steric tolerance imposed by the sigma 3 receptor.
|
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 10 uM
|
Cavia porcellus
|
54.6
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
|
Compound was tested for its ability to inhibit specific binding of [3H]-clonidine to alpha-2-adrenoceptor.
|
None
|
37.5
nM
|
|
Journal : J. Med. Chem.
Title : Two stereoisomeric imidazoline derivatives: synthesis and optical and alpha 2-adrenoceptor activities.
Year : 1986
Volume : 29
Issue : 7
First Page : 1183
Last Page : 1188
Authors : Biedermann J, León-Lomelí A, Borbe HO, Prop G.
Abstract : Two eight-step pathways for synthesizing the stereoisomeric compounds (-)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("levlofexidine" hydrochloride; (-)-lofexidine hydrochloride) and (+)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("dexlofexidine" hydrochloride; (+)-lofexidine hydrochloride) and the optical resolution of (+/-)-lofexidine are described. (-)-Lofexidine, a stereoselective alpha 2-adrenoceptor agonist, due to its center of asymmetry, is demonstrated to be a potent drug for the treatment of hypertension (doses 0.561 microgram/kg) and to have the highest affinity and a concentration dependency for alpha 2-adrenoceptors in direct binding studies (0.36 nmol/L). (+)-Lofexidine is 10 times less potent.
|
Binding affinity towards alpha-1A adrenergic receptor expressed in human embryonic kidney (HEK293) cells
|
Homo sapiens
|
4.12
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.
Year : 2005
Volume : 15
Issue : 21
First Page : 4691
Last Page : 4695
Authors : Hong SS, Bavadekar SA, Lee SI, Patil PN, Lalchandani SG, Feller DR, Miller DD.
Abstract : The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.
|
Binding affinity towards human alpha-1B adrenergic receptor expressed in Chinese Hamster ovary (CHO) cells
|
Homo sapiens
|
47.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.
Year : 2005
Volume : 15
Issue : 21
First Page : 4691
Last Page : 4695
Authors : Hong SS, Bavadekar SA, Lee SI, Patil PN, Lalchandani SG, Feller DR, Miller DD.
Abstract : The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.
|
Binding affinity towards human alpha-1D adrenergic receptor expressed in Chinese Hamster ovary (CHO) cells
|
Homo sapiens
|
19.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.
Year : 2005
Volume : 15
Issue : 21
First Page : 4691
Last Page : 4695
Authors : Hong SS, Bavadekar SA, Lee SI, Patil PN, Lalchandani SG, Feller DR, Miller DD.
Abstract : The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.
|
Binding affinity towards human alpha-2A adrenergic receptor expressed in Chinese Hamster ovary (CHO) cells
|
Homo sapiens
|
55.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.
Year : 2005
Volume : 15
Issue : 21
First Page : 4691
Last Page : 4695
Authors : Hong SS, Bavadekar SA, Lee SI, Patil PN, Lalchandani SG, Feller DR, Miller DD.
Abstract : The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.
|
Binding affinity towards human alpha-2B adrenergic receptor expressed in Chinese Hamster ovary (CHO) cells
|
Homo sapiens
|
48.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.
Year : 2005
Volume : 15
Issue : 21
First Page : 4691
Last Page : 4695
Authors : Hong SS, Bavadekar SA, Lee SI, Patil PN, Lalchandani SG, Feller DR, Miller DD.
Abstract : The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.
|
Binding affinity towards human alpha-2C adrenergic receptor expressed in Chinese Hamster ovary (CHO) cells
|
Homo sapiens
|
80.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.
Year : 2005
Volume : 15
Issue : 21
First Page : 4691
Last Page : 4695
Authors : Hong SS, Bavadekar SA, Lee SI, Patil PN, Lalchandani SG, Feller DR, Miller DD.
Abstract : The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.
|
Displacement of [3H]prazosin from alpha1 adrenergic receptor
|
None
|
13.0
nM
|
|
Journal : J. Nat. Prod.
Title : The role of receptor binding in drug discovery.
Year : 1993
Volume : 56
Issue : 4
First Page : 441
Last Page : 455
Authors : Sweetnam PM, Caldwell L, Lancaster J, Bauer C, McMillan B, Kinnier WJ, Price CH.
Abstract : Radioligand receptor binding has been used extensively to identify and characterize a host of receptors and enzymes targeting virtually every therapeutic area. Many drug discovery programs have been based on the utilization of radioligand receptor binding technology to identify lead compounds which interact with receptors likely to be important in neuronal, immunological, gastrointestinal, and cardiovascular function/dysfunction. There are several obvious advantages to using in vitro receptor binding as a first level screen when compared to in vivo pharmacometric screens. Scientifically, the structure activity data generated in binding assays is a direct reflection of the ligand/receptor interaction minus the complications which result from secondary events, bioavailability, and pharmacodynamic issues. Technically, the binding studies require only a small amount of test compound (< or = 1 mg), while whole animal studies routinely need gram quantities. Similarly, only a small amount of tissue is required, compared with the cost of purchase and maintenance of live animals for in vivo screening. Supply and labor costs are drastically reduced due to the limited volume and test tube based technology of receptor binding. For these reasons receptor binding assays have been utilized with considerable success to discover site specific lead compounds in virtually every therapeutic area.
|
Displacement of [3H]RX781094 from alpha2 adrenergic receptor
|
None
|
1.7
nM
|
|
Journal : J. Nat. Prod.
Title : The role of receptor binding in drug discovery.
Year : 1993
Volume : 56
Issue : 4
First Page : 441
Last Page : 455
Authors : Sweetnam PM, Caldwell L, Lancaster J, Bauer C, McMillan B, Kinnier WJ, Price CH.
Abstract : Radioligand receptor binding has been used extensively to identify and characterize a host of receptors and enzymes targeting virtually every therapeutic area. Many drug discovery programs have been based on the utilization of radioligand receptor binding technology to identify lead compounds which interact with receptors likely to be important in neuronal, immunological, gastrointestinal, and cardiovascular function/dysfunction. There are several obvious advantages to using in vitro receptor binding as a first level screen when compared to in vivo pharmacometric screens. Scientifically, the structure activity data generated in binding assays is a direct reflection of the ligand/receptor interaction minus the complications which result from secondary events, bioavailability, and pharmacodynamic issues. Technically, the binding studies require only a small amount of test compound (< or = 1 mg), while whole animal studies routinely need gram quantities. Similarly, only a small amount of tissue is required, compared with the cost of purchase and maintenance of live animals for in vivo screening. Supply and labor costs are drastically reduced due to the limited volume and test tube based technology of receptor binding. For these reasons receptor binding assays have been utilized with considerable success to discover site specific lead compounds in virtually every therapeutic area.
|
Displacement of [125I]PIC from human alpha2 adrenoceptors expressed in CHO cells
|
Homo sapiens
|
57.03
nM
|
|
Journal : Bioorg. Med. Chem.
Title : QSAR study of imidazoline antihypertensive drugs.
Year : 2008
Volume : 16
Issue : 15
First Page : 7134
Last Page : 7140
Authors : Nikolic K, Filipic S, Agbaba D.
Abstract : The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I(1)-R). Selective I(1)-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I(1) receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I(1)-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d,p) and Becke3LYP/6-31G(d,p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistically significant model with R(2)=0.935 and cross-validation parameter q(2)(pre) =0.803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I(1)-R ligands were aimed to link the structures to their reported I(1)-R binding affinity log(1/K(i)). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I(1) receptors. The developed QSAR model is intended to predict I(1)-R binding affinity of related compounds and to define possible physicochemical, electrical, and structural requirements for selective I(1)-receptor ligands.
|
Displacement of [125I]PIC from human imidazoline receptor 1 in human platelets analyzed under norepinephrine mask of alpha 2AR
|
Homo sapiens
|
11.4
nM
|
|
Displacement of [125I]PIC from human imidazoline receptor 1 in human platelets analyzed under norepinephrine mask of alpha 2AR
|
Homo sapiens
|
11.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : QSAR study of imidazoline antihypertensive drugs.
Year : 2008
Volume : 16
Issue : 15
First Page : 7134
Last Page : 7140
Authors : Nikolic K, Filipic S, Agbaba D.
Abstract : The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I(1)-R). Selective I(1)-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I(1) receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I(1)-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d,p) and Becke3LYP/6-31G(d,p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistically significant model with R(2)=0.935 and cross-validation parameter q(2)(pre) =0.803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I(1)-R ligands were aimed to link the structures to their reported I(1)-R binding affinity log(1/K(i)). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I(1) receptors. The developed QSAR model is intended to predict I(1)-R binding affinity of related compounds and to define possible physicochemical, electrical, and structural requirements for selective I(1)-receptor ligands.
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
359.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
103.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
11.0
nM
|
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
4.655
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
82.0
nM
|
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
45.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
22.0
nM
|
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
11.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
6.0
nM
|
|
DRUGMATRIX: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
2.25
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
18.0
nM
|
|
DRUGMATRIX: Alpha-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
8.228
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
110.0
nM
|
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
16.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
396.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
207.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
746.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
725.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
58.0
nM
|
|
DRUGMATRIX: Imidazoline I2, Central radioligand binding (ligand: [3H] Idazoxan)
|
Rattus norvegicus
|
39.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Displacement of [3H]prazosin from alpha1 adrenoceptor in rat cerebral cortex after 30 mins by beta scintillation counting
|
Rattus norvegicus
|
10.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α₁-adrenoceptor antagonistic properties.
Year : 2012
Volume : 20
Issue : 14
First Page : 4245
Last Page : 4257
Authors : Handzlik J, Szymańska E, Wójcik R, Dela A, Jastrzębska-Więsek M, Karolak-Wojciechowska J, Fruziński A, Siwek A, Filipek B, Kieć-Kononowicz K.
Abstract : The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α(1)-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a-18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro's pharmacophore model and structural properties of previously investigated α(1)-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α(1)-ARs in nanomolar range (40-290 nM). The highest activities (K(i)<75 nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of α(1)-affinities as follows: 3,4-di CH(3)O>2,4-di CH(3)O>4-Cl>2,3-di CH(3)O>H>4-N(CH(3))(2).
|
Displacement of [3H]prazoin from rat cerebral cortex adrenergic alpha1 receptor
|
Rattus norvegicus
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on the 1-(2-biphenyl)piperazine motif: identification of new potent and selective ligands for the serotonin(7) (5-HT(7)) receptor with agonist or antagonist action in vitro or ex vivo.
Year : 2012
Volume : 55
Issue : 14
First Page : 6375
Last Page : 6380
Authors : Lacivita E, Patarnello D, Stroth N, Caroli A, Niso M, Contino M, De Giorgio P, Di Pilato P, Colabufo NA, Berardi F, Perrone R, Svenningsson P, Hedlund PB, Leopoldo M.
Abstract : Here we report the design, synthesis, and 5-HT(7) receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT(7) affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT(7) affinities in the nanomolar range and >100-fold selectivity over 5-HT(1A) and adrenergic α(1) receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (9a) showed 5-HT(7) agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT(7)-expressing HeLa cells.
|
Displacement of [3H]prazosin from alpha1-adrenergic receptor in rat cerebral cortex after 30 mins by scintillation counting
|
Rattus norvegicus
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety.
Year : 2013
Volume : 23
Issue : 15
First Page : 4419
Last Page : 4423
Authors : Waszkielewicz AM, Gunia A, Szkaradek N, Pytka K, Siwek A, Satała G, Bojarski AJ, Szneler E, Marona H.
Abstract : A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT₁A, 5-HT₆ and 5-HT₇b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT₁A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.
|
Displacement of [3H]prazosin from alpha1 adrenergic receptor in rat cerebral cortex after 30 mins by Microbeta scintillation counting analysis
|
Rattus norvegicus
|
10.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : SAR-studies on the importance of aromatic ring topologies in search for selective 5-HT(7) receptor ligands among phenylpiperazine hydantoin derivatives.
Year : 2014
Volume : 78
First Page : 324
Last Page : 339
Authors : Handzlik J, Bojarski AJ, Satała G, Kubacka M, Sadek B, Ashoor A, Siwek A, Więcek M, Kucwaj K, Filipek B, Kieć-Kononowicz K.
Abstract : The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer-Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT1A, 5-HT6, 5-HT7 and α1-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT3A expressed in Xenopus Oocytes as well as on their activity at α1-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α1-ARs, 5-HT1A, 5-HT7 (Ki ∼ 0.8-353 nM) significantly higher than those for 5-HT6 receptors. Very weak inhibitory effect at 5-HT3A accompanied with high activity at α1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT7 affinity with Ki = 3 nM and selectivity with 40-3600 fold towards 5-HT1A, 5-HT6, and α1-ARs.
|
Displacement of [3H]prazosin from rat cerebral cortex alpha-1 adrenergic receptor by liquid scintillation counting analysis
|
Rattus norvegicus
|
23.44
nM
|
|
Journal : Bioorg. Med. Chem.
Title : α-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one.
Year : 2015
Volume : 23
Issue : 9
First Page : 2104
Last Page : 2111
Authors : Zaręba P, Dudek M, Lustyk K, Siwek A, Starowicz G, Bednarski M, Nowiński L, Raźny K, Sapa J, Malawska B, Kulig K.
Abstract : This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for α₁- and α₂-adrenoceptors were assessed. The compound with highest affinity for the α₁-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10 h) with pKi=7.30. Compound with pKi (α₁) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α₁A- and α₁B-adrenoceptors. All compounds tested were antagonists of the α₁B-adrenoceptors. Additionally, compounds 10e and 10h were α₁A-adrenoceptors antagonist. The dual α₁A-/α₁B-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0 mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour.
|
Displacement of [3H]-Prazosin from human alpha-1A adrenergic receptor transfected in CHO cell membranes after 2 hrs by microplate scintillation counting analysis
|
Homo sapiens
|
1.1
nM
|
|
Displacement of [3H]-Prazosin from human alpha-1A adrenergic receptor transfected in CHO cell membranes after 2 hrs by microplate scintillation counting analysis
|
Homo sapiens
|
0.6
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Quinazoline-Based Fluorescent Probes to α1-Adrenergic Receptors.
Year : 2015
Volume : 6
Issue : 5
First Page : 502
Last Page : 506
Authors : Zhang W, Ma Z, Li W, Li G, Chen L, Liu Z, Du L, Li M.
Abstract : α1-Adrenergic receptors (α1-ARs), as the essential members of G protein-coupled receptors (GPCRs), can mediate numerous physiological responses in the sympathetic nervous system. In the current research, a series of quinazoline-based small-molecule fluorescent probes to α1-ARs (1a-1e), including two parts, a pharmacophore for α1-AR recognition and a fluorophore for visualization, were well designed and synthesized. The biological evaluation results displayed that these probes held reasonable fluorescent properties, high affinity, accepted cell toxicity, and excellent subcellular localization imaging potential for α1-ARs.
|
Displacement of [3H]-Prazosin from human alpha-1B adrenergic receptor transfected in CHO cell membranes after 2 hrs by microplate scintillation counting analysis
|
Homo sapiens
|
10.8
nM
|
|
Displacement of [3H]-Prazosin from human alpha-1B adrenergic receptor transfected in CHO cell membranes after 2 hrs by microplate scintillation counting analysis
|
Homo sapiens
|
4.8
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Quinazoline-Based Fluorescent Probes to α1-Adrenergic Receptors.
Year : 2015
Volume : 6
Issue : 5
First Page : 502
Last Page : 506
Authors : Zhang W, Ma Z, Li W, Li G, Chen L, Liu Z, Du L, Li M.
Abstract : α1-Adrenergic receptors (α1-ARs), as the essential members of G protein-coupled receptors (GPCRs), can mediate numerous physiological responses in the sympathetic nervous system. In the current research, a series of quinazoline-based small-molecule fluorescent probes to α1-ARs (1a-1e), including two parts, a pharmacophore for α1-AR recognition and a fluorophore for visualization, were well designed and synthesized. The biological evaluation results displayed that these probes held reasonable fluorescent properties, high affinity, accepted cell toxicity, and excellent subcellular localization imaging potential for α1-ARs.
|
Displacement of [3H]-Prazosin from human alpha-1D adrenergic receptor transfected in CHO cell membranes after 2 hrs by microplate scintillation counting analysis
|
Homo sapiens
|
12.5
nM
|
|
Displacement of [3H]-Prazosin from human alpha-1D adrenergic receptor transfected in CHO cell membranes after 2 hrs by microplate scintillation counting analysis
|
Homo sapiens
|
7.6
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Quinazoline-Based Fluorescent Probes to α1-Adrenergic Receptors.
Year : 2015
Volume : 6
Issue : 5
First Page : 502
Last Page : 506
Authors : Zhang W, Ma Z, Li W, Li G, Chen L, Liu Z, Du L, Li M.
Abstract : α1-Adrenergic receptors (α1-ARs), as the essential members of G protein-coupled receptors (GPCRs), can mediate numerous physiological responses in the sympathetic nervous system. In the current research, a series of quinazoline-based small-molecule fluorescent probes to α1-ARs (1a-1e), including two parts, a pharmacophore for α1-AR recognition and a fluorophore for visualization, were well designed and synthesized. The biological evaluation results displayed that these probes held reasonable fluorescent properties, high affinity, accepted cell toxicity, and excellent subcellular localization imaging potential for α1-ARs.
|
Displacement of [3H]prazosin from alpha1 adrenergic receptor in rat brain cerebral cortex after 30 mins by microbeta scintillation counting method
|
Rattus norvegicus
|
18.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and activity of newly designed aroxyalkyl or aroxyethoxyethyl derivatives of piperazine on the cardiovascular and the central nervous systems.
Year : 2016
Volume : 26
Issue : 21
First Page : 5315
Last Page : 5321
Authors : Waszkielewicz AM, Kubacka M, Pańczyk K, Mogilski S, Siwek A, Głuch-Lutwin M, Gryboś A, Filipek B.
Abstract : In the search for new hypotensive agents some new aroxyalkyl or aroxyethoxyethyl derivatives of piperazine have been synthesized and evaluated for their pharmacological properties. Pharmacological tests included receptor binding assays toward adrenergic receptors α1, α2 and β1, additionally 5-HT1A, functional bioassay and in vivo evaluation of hypotensive activity as well as antidepressant-like potential. All the tested compounds exhibited α1-antagonistic properties, three of them possessed also hypotensive activity in rats. The most promising compound 3 1-[4-(2,6-dimethylphenoxy)butyl]-4-(2-methoxyphenyl)piperazine hydrochloride was a selective α1 receptor antagonist (Ki=23.5±1.3, α1/α2=15.77, pKB=8.538±0.109). It was active in all tested doses in vivo (1, 0.5, and 0.1mg/kg) and it reduced blood pressure by 10-13% at the dose of 1mg/kg (rats, i.v.). Compound 5 1-[2-(2,3-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine dihydrochloride exhibited the lowest dose for antidepressant-like activity 5mg/kgb.w. (mice, i.p.) without influence on spontaneous activity (mice, i.p.).
|
Displacement of [3H]-prazosin from alpha1-adrenergic receptor in rat brain cortex after 30 mins by Microbeta scintillation counting method
|
Rattus norvegicus
|
16.0
nM
|
|
Journal : Eur J Med Chem
Title : Computer-aided insights into receptor-ligand interaction for novel 5-arylhydantoin derivatives as serotonin 5-HT7 receptor agents with antidepressant activity.
Year : 2018
Volume : 147
First Page : 102
Last Page : 114
Authors : Kucwaj-Brysz K, Kurczab R, Jastrzębska-Więsek M, Żesławska E, Satała G, Nitek W, Partyka A, Siwek A, Jankowska A, Wesołowska A, Kieć-Kononowicz K, Handzlik J.
Abstract : This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT7 receptor (5-HT7R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT7R and selectivity over 5-HT1AR, dopamine D2R and α1-, α2-and β-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT7R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12,Ki ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds (5-8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT7R affinity than the di-phenyl ones.
|
Displacement of [3H]prazosin from recombinant human alpha1 adrenoceptor expressed in CHO cell membranes after 30 mins by liquid scintillation counting method
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system.
Year : 2018
Volume : 28
Issue : 11
First Page : 2039
Last Page : 2049
Authors : Pańczyk K, Pytka K, Jakubczyk M, Rapacz A, Sałat K, Furgała A, Siwek A, Głuch-Lutwin M, Gryboś A, Słoczyńska K, Pękala E, Żmudzki P, Bucki A, Kołaczkowski M, Żelaszczyk D, Marona H, Waszkielewicz AM.
Abstract : Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as - at higher doses - for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
2.09
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-2.29
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
6.34
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
4.16
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
34.66
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.06
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-2.31
%
|
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.21
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.13
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.13
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Displacement of [3H]-pyrilamine from human recombinant histamine H1 receptor expressed in human recombinant CHO-K1 cells at 1 uM incubated for 60 mins by solid scintillation counting method relative to control
|
Homo sapiens
|
91.0
%
|
|
