|
Compound was tested in vitro for binding affinity towards delta opioid receptor by measuring displacement of [3H]DPDPE from guinea pig brain membranes
|
Cavia porcellus
|
187.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Octahydro-1,2,3,4,4a,5,11,11a-pyrido[3,4-c][1,5]benzoxazepines: conformationally restricted fentanyl analogs
Year : 1995
Volume : 5
Issue : 11
First Page : 1177
Last Page : 1182
Authors : Kudzma LV, Evans SM, Turnbull SP, Severnak SA, Ezell EF
|
Inhibition of electrically evoked contraction in guinea pig ileum determined in vitro
|
Cavia porcellus
|
1.76
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.
Year : 1991
Volume : 34
Issue : 7
First Page : 2202
Last Page : 2208
Authors : Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ.
Abstract : In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.
|
Inhibition of opioid activity in electricaly stimulated myenteric plexus longitudinal muscle of guinea pig ileum(GPI) preparation
|
Cavia porcellus
|
3.45
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 1- and 2-substituted fentanyl analogues for opioid activity.
Year : 1983
Volume : 26
Issue : 3
First Page : 348
Last Page : 352
Authors : Essawi MY, Portoghese PS.
Abstract : We synthesized fentanyl analogues that possess key groups common to the opioid peptides to investigate whether or not these two classes of compounds interact with common subsites on opioid receptors. The design of the analogues was based on the possibility of structural analogy between the two aromatic rings of fentanyl and the Tyr1 and Phe4 residues of the opioid peptides. The synthesized compounds showed very weak or no opioid activity as tested in the electrically stimulated longitudinal muscle of the guinea pig ileum or mouse vas deferens preparations. These results, together with those of reported studies, suggest that fentanyl and the opioid peptides interact with different subsites on either mu or sigma receptors. Studies using the irreversible mu opioid receptor antagonist, beta-funaltrexamine, indicate that fentanyl interacts preferentially with mu opioid receptors.
|
Inhibition of the electrically induced muscle contractions was determined using the guinea pig ileum
|
Cavia porcellus
|
4.5
nM
|
|
Journal : J. Med. Chem.
Title : 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors.
Year : 2003
Volume : 46
Issue : 4
First Page : 623
Last Page : 633
Authors : Bishop MJ, Garrido DM, Boswell GE, Collins MA, Harris PA, McNutt RW, O'Neill SJ, Wei K, Chang KJ.
Abstract : Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.
|
Inhibition of opioid activity in electricaly stimulated myenteric plexus longitudinal muscle of mouse vas deferens(MVD) preparation
|
Mus musculus
|
9.45
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 1- and 2-substituted fentanyl analogues for opioid activity.
Year : 1983
Volume : 26
Issue : 3
First Page : 348
Last Page : 352
Authors : Essawi MY, Portoghese PS.
Abstract : We synthesized fentanyl analogues that possess key groups common to the opioid peptides to investigate whether or not these two classes of compounds interact with common subsites on opioid receptors. The design of the analogues was based on the possibility of structural analogy between the two aromatic rings of fentanyl and the Tyr1 and Phe4 residues of the opioid peptides. The synthesized compounds showed very weak or no opioid activity as tested in the electrically stimulated longitudinal muscle of the guinea pig ileum or mouse vas deferens preparations. These results, together with those of reported studies, suggest that fentanyl and the opioid peptides interact with different subsites on either mu or sigma receptors. Studies using the irreversible mu opioid receptor antagonist, beta-funaltrexamine, indicate that fentanyl interacts preferentially with mu opioid receptors.
|
Inhibition of the electrically induced muscle contractions was determined using the mouse vas deferens
|
Mus musculus
|
490.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors.
Year : 2003
Volume : 46
Issue : 4
First Page : 623
Last Page : 633
Authors : Bishop MJ, Garrido DM, Boswell GE, Collins MA, Harris PA, McNutt RW, O'Neill SJ, Wei K, Chang KJ.
Abstract : Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.
|
Compound was tested in vitro for binding affinity towards mu opioid receptor by measuring displacement of [3H]DAGO from guinea pig brain membranes
|
Cavia porcellus
|
3.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Octahydro-1,2,3,4,4a,5,11,11a-pyrido[3,4-c][1,5]benzoxazepines: conformationally restricted fentanyl analogs
Year : 1995
Volume : 5
Issue : 11
First Page : 1177
Last Page : 1182
Authors : Kudzma LV, Evans SM, Turnbull SP, Severnak SA, Ezell EF
|
Binding affinity against delta-opiate receptor (human) using [3H]-DPDPE radioligand
|
None
|
431.0
nM
|
|
Journal : J. Med. Chem.
Title : From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.
Year : 2001
Volume : 44
Issue : 21
First Page : 3378
Last Page : 3390
Authors : Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Déprez B.
Abstract : Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.
|
Binding affinity against Opioid receptor kappa 1
|
None
|
196.5
nM
|
|
Journal : J. Med. Chem.
Title : Molecular docking reveals a novel binding site model for fentanyl at the mu-opioid receptor.
Year : 2000
Volume : 43
Issue : 3
First Page : 381
Last Page : 391
Authors : Subramanian G, Paterlini MG, Portoghese PS, Ferguson DM.
Abstract : The ligand binding modes of a series of fentanyl derivatives are examined using a combination of conformational analysis and molecular docking to the mu-opioid receptor. Condensed-phase molecular dynamics simulations are applied to evaluate potential relationships between ligand conformation and fentanyl substitution and to generate probable "bioactive" structures for the ligand series. Automated docking of the largely populated solution conformers identified a common binding site orientation that places the N-phenethyl group of fentanyl deep in a crevice between transmembrane (TM) helices II and III while the N-phenylpropanamide group projected toward a pocket formed by TM-III, -VI, and -VII domains. An analysis of the binding modes indicates the most potent fentanyl derivatives adopt an extended conformation both in solution and in the bound state, suggesting binding affinity may depend on the conformational preferences of the ligands. The results are consistent with ligand binding data derived from chimeric and mutant receptor studies as well as structure-activity relationship data reported on a wide range of fentanyl analogues. The binding site model is also compared to that of N-phenethylnormorphine. An overlay of the bound conformation of the opiate and cis-3-methylfentanyl shows the N-phenethyl groups occupy equivalent binding domains in the receptor. While the cationic amines of both ligand classes were found docked to an established anchor site (D149 in TM-III), no overlap was observed between the N-phenylpropanamide group and the remaining components of the opiate scaffold. The unique binding mode(s) proposed for the fentanyl series may, in part, explain the difficulties encountered in defining models of recognition at the mu-receptor and suggest opioid receptors may display multiple binding epitopes. Furthermore, the results provide new insight to the design of experiments aimed at understanding the structural basis to the differential selectivities of ligands at the mu-, delta-, and kappa-opioid receptors.
|
In vitro binding activity against opioid receptor mu using [3H]-DAGO as radioligand
|
Cavia porcellus
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics.
Year : 1991
Volume : 34
Issue : 2
First Page : 827
Last Page : 841
Authors : Bagley JR, Thomas SA, Rudo FG, Spencer HK, Doorley BM, Ossipov MH, Jerussi TP, Benvenga MJ, Spaulding T.
Abstract : A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics. Compound 9A (methyl 1-[2-(1H-pyrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4- piperidinecarboxylate), which exhibited appreciable mu-opioid receptor affinity, was a more potent and short-acting analgesic, than alfentanil with less respiratory depression in the rat. On the other hand, the phthalimides 57A and 57B, which exhibited negligible affinity for opioid receptors associated with the mediation of nociceptive transmission (i.e., mu-, kappa-, and delta-subtypes), displayed analgesic efficacy in all antinociception tests. In addition, while 57B, compared to clinical opioids, showed a superior recovery of motor coordination after regaining of righting reflex from full anesthetic doses in the rat rotorod test, 57A showed significantly less depression of cardiovascular function at supraanalgesic doses in the isoflurane-anesthetized rat.
|
In vivo binding affinity to opioid receptor preparations from rat brain
|
None
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Probes for narcotic receptor mediated phenomena. 12. cis-(+)-3-Methylfentanyl isothiocyanate, a potent site-directed acylating agent for delta opioid receptors. Synthesis, absolute configuration, and receptor enantioselectivity.
Year : 1986
Volume : 29
Issue : 6
First Page : 1087
Last Page : 1093
Authors : Burke TR, Jacobson AE, Rice KC, Silverton JV, Simonds WF, Streaty RA, Klee WA.
Abstract : The first enantiomeric pair of irreversible opioid ligands [(+)- and (-)-4] were synthesized in greater than 99.6% optical purity as determined by HPLC analysis of diastereoisomeric derivatives of the intermediate 3-methyl-N-phenyl-4-piperidinamine enantiomers. Single-crystal X-ray analysis of the (R,R)-L-(+)-tartaric acid salt of (-)-9 revealed the absolute configuration to be 3S,4R. The absolute configuration of (-)-3 [cis-(-)-3-methylfentanyl] and (-)-4 derived from (-)-9 is thus 3S,4R and that of (+)-3 and (+)-4 is 3R,4S. The (+) enantiomer of 4 (SUPERFIT) was shown to be highly potent and specific for acylation of delta opioid receptors (to the exclusion of mu) in rat brain membranes like its achiral prototype FIT and was about 10 times as potent as the latter in this assay. The (+)-4 was about 5 times as potent as FIT in acylation of delta receptors in NG108-15 neuroblastoma X glioma hybrid cells and about 50 times as potent as its enantiomer. Both FIT and (+)-4 behaved as partial agonists in inhibition of delta receptor coupled adenylate cyclase in NG108-15 membranes and (+)-4 was 5-10 times more potent than FIT and about 100 times more potent than its enantiomer in this assay. Dibromination of amine 12, catalytic exchange of bromine with tritium gas, and reaction of the labeled amine with thiophosgene afforded [3H]-(+)-4 with a specific activity of 13 Ci/mmol. Previous experiments indicated (+)-4 acylates the same 58 000-dalton glycoprotein previously shown to be acylated by FIT but with less nonspecific labeling. In view of the high potency and specificity of (+)-4 and the availability of its enantiomer, it seems likely that these compounds will prove to be valuable tools for study of the opioid receptor complex.
|
In vitro binding activity against opioid receptor delta using [3DPDPE] as radioligand
|
Cavia porcellus
|
187.4
nM
|
|
Journal : J. Med. Chem.
Title : New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics.
Year : 1991
Volume : 34
Issue : 2
First Page : 827
Last Page : 841
Authors : Bagley JR, Thomas SA, Rudo FG, Spencer HK, Doorley BM, Ossipov MH, Jerussi TP, Benvenga MJ, Spaulding T.
Abstract : A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics. Compound 9A (methyl 1-[2-(1H-pyrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4- piperidinecarboxylate), which exhibited appreciable mu-opioid receptor affinity, was a more potent and short-acting analgesic, than alfentanil with less respiratory depression in the rat. On the other hand, the phthalimides 57A and 57B, which exhibited negligible affinity for opioid receptors associated with the mediation of nociceptive transmission (i.e., mu-, kappa-, and delta-subtypes), displayed analgesic efficacy in all antinociception tests. In addition, while 57B, compared to clinical opioids, showed a superior recovery of motor coordination after regaining of righting reflex from full anesthetic doses in the rat rotorod test, 57A showed significantly less depression of cardiovascular function at supraanalgesic doses in the isoflurane-anesthetized rat.
|
Binding affinity towards Opioid receptor kappa 1 using [3H]U-69593 as radioligand.
|
Cavia porcellus
|
196.5
nM
|
|
Journal : J. Med. Chem.
Title : Enantiomers of diastereomeric cis-N-[1-(2-hydroxy-2-phenylethyl)- 3-methyl-4-piperidyl]-N-phenylpropanamides: synthesis, X-ray analysis, and biological activities.
Year : 1995
Volume : 38
Issue : 9
First Page : 1547
Last Page : 1557
Authors : Brine GA, Stark PA, Liu Y, Carroll FI, Singh P, Xu H, Rothman RB.
Abstract : (+/-)-cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide (1) is a mixture of four stereoisomers [(2S,3R,4S)-1a, (2R,3R,4S)-1b, (2R,3S,4R)-1c, and (2S,3S,4R)-1d], which together constitute two diastereoisomeric pairs of optical isomers. These four stereoisomers were prepared from optically active intermediates of known absolute configuration by procedures which had no effect on the configurations of the piperidine 3- and 4-carbons. The configuration of the phenylethyl 2-carbon in the final products was determined by X-ray analysis of (2S,3S,4R)-1d. A 1H NMR comparison of the final products to ohmefentanyl established that the racemic pair previously known as ohmefentanyl was a mixture of (2S,3R,4S)-1a and (2R,3S,4R)-1c. The individual activities of 1a, 1b, 1c, and 1d were evaluated in a variety of binding and pharmacological assays. The binding data revealed that isomers 1b and 1c had the highest affinity and selectivity for the mu site labeled with [3H]DAMGO. In contrast, the four isomers displaced [3H]etorphine in the order 1a approximately 1b > 1c approximately 1d. Evaluation of the four isomers on the mouse vas deferens (MVD) preparation revealed a potency order of 1a > 1b > 1c > 1d with concentrations of 1a and 1b in the femtomolar range causing inhibition. Experiments using the antagonists naltrexone (mu), ICI 174864 (delta), and norbinaltorphimine (kappa) demonstrated that the effects of 1a were mediated largely by the mu receptor while both delta and kappa agonist effects contributed to the actions of 1b and 1c. Isomer 1d acted as a weak mu antagonist in the MVD preparation. The same potency order was observed in a mouse analgesic assay and a rhesus monkey single dose suppression study. From the latter study the potency of 1a was estimated to be 20,000-50,000 times that of morphine, making this isomer one of the most potent opiates known. In the rhesus monkey study, isomer 1d failed to substitute for morphine and seemed to exacerbate withdrawal at doses of 0.6, 3.0, and 6.0 mg/kg. On the basis of the mouse data, isomer 1a was 21,000 times more potent than 1d, whereas isomers 1b and 1c were similar in their opiate activity in vivo. Using the optical isomers of cis-3-methylfentanyl as reference compounds, we analyzed the effects on the pharmacological activities of introducing a phenylethyl 2-hydroxyl group into the molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
|
Binding affinity of compound evaluated for Opioid receptor delta 1 isolated from rat brain
|
None
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors.
Year : 2003
Volume : 46
Issue : 4
First Page : 623
Last Page : 633
Authors : Bishop MJ, Garrido DM, Boswell GE, Collins MA, Harris PA, McNutt RW, O'Neill SJ, Wei K, Chang KJ.
Abstract : Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.
|
Binding affinity against Opioid receptor delta 1 in guinea pig brain membranes
|
Cavia porcellus
|
679.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models.
Year : 1998
Volume : 8
Issue : 19
First Page : 2685
Last Page : 2688
Authors : Wang C, McFadyen IJ, Traynor JR, Mosberg HI.
Abstract : A pair of diastereomeric peptidomimetics based upon opioid receptor-binding pharmacophore models derived for a series of opioid tetrapeptides was synthesized. Both analogues display high opioid receptor affinity, moderate selectivity for the mu opioid receptor, and are potent, full agonists.
|
Displacement of [3H]naloxone from rat brain Opioid receptors
|
Rattus norvegicus
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and stereochemistry of 7-phenyl-2-propionanilidobenzo[a]quinolizidine derivatives. Structural probes of fentanyl analgesics.
Year : 1981
Volume : 24
Issue : 1
First Page : 79
Last Page : 88
Authors : Maryanoff BE, McComsey DF, Taylor RJ, Gardocki JF.
Abstract : The for diastereomers of N-(1,3,4,6,7,11b-hexahydro-7-phenyl-2H-benzo[a]quinolizin-2-yl)-N-phenylpropanamide (7c, 7d, 9c, and 9d), which are conformationally restricted analogues of fentanyl, were synthesized and separately tested for analgesic activity and affinity for the opiate receptor of rat brain. Stereochemical assignments for 7c, 7d, 9c, and 9d were deduced from NMR spectral analyses. Conformational analysis revealed that the 2 alpha isomers (7d and 9d) exist in solution as mixtures of cis- and trans-fused conformers with ca. 90 and 45% cis form, respectively. Other compounds (12a, 12b, and 14) related to these propionanilides were also prepared, stereochemically characterized, and tested. Weak analgesic activity was observed for 7d, and both 7d and 9d bound to the opiate receptor with an I50 of ca. 1100 and 1500 nM, respectively (ca. 0.5% of fentanyl and 2% of morphine). The analgesic activity of 7d was abolished by the opiate antagonist naloxone.
|
Binding affinity to opioid receptors by the displacement of [3H]fentanyl in rat brain homogenates
|
None
|
1.14
nM
|
|
Journal : J. Med. Chem.
Title : Opiate receptor interaction of compounds derived from or structurally related to fentanyl.
Year : 1981
Volume : 24
Issue : 7
First Page : 777
Last Page : 782
Authors : Lobbezoo MW, Soudijn W, van Wijngaarden I.
Abstract : The opiate receptor affinity of compounds derived from or structurally related to fentanyl (1) was determined by in vitro receptor binding assays. The relatively high affinity of fentanyl (3 times morphine) was hardly influenced by the introduction of a 2-CH3, 2-OCH3, or a 2-Cl substituent into the anilino phenyl and was moderately reduced by 2-C2H5, 2-OC2H5, and 2,6-(CH3)2 substitution in this ring. Removal of the n-propionyl g in vitro receptor binding assays. The relatively high affinity of fentanyl (3 times morphine) was hardly influenced by the introduction of a 2-CH3, 2-OCH3, or a 2-Cl substituent into the anilino phenyl and was moderately reduced by 2-C2H5, 2-OC2H5, and 2,6-(CH3)2 substitution in this ring. Removal of the n-propionyl g in vitro receptor binding assays. The relatively high affinity of fentanyl (3 times morphine) was hardly influenced by the introduction of a 2-CH3, 2-OCH3, or a 2-Cl substituent into the anilino phenyl and was moderately reduced by 2-C2H5, 2-OC2H5, and 2,6-(CH3)2 substitution in this ring. Removal of the n-propionyl group of the 2-OCH3 derivative, fixation of the anilino phenyl in fentanyl to the propionyl group or the piperidine ring, and replacement of the amide N by C all caused a sharp decline of receptor affinity. Examination of molecular models seemed to indicate that optimal opiate receptor interaction of fentanyl and its derivatives requires a virtually perpendicular position of the anilino phenyl with respect to the amide function.
|
Displacement of [3H]nalotrexone from rat-brain Opioid receptors
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Potential affinity labels for the opiate receptor based on fentanyl and related compounds.
Year : 1982
Volume : 25
Issue : 8
First Page : 913
Last Page : 919
Authors : Maryanoff BE, Simon EJ, Gioannini T, Gorissen H.
Abstract : Derivatives of fentanyl, 3-methylfentanyl, sufentanil, and lofentanil, possessing chemo- or photoaffinity functionalities, were synthesized as potential affinity reagents for the opiate receptor. Opiate receptor binding constants (IC50) were determined in competition experiments with [3H]naloxone and [3H]naltrexone. Affinity-labeling experiments were generally unsuccessful, although some irreversible attachment was achieved with alpha-diazoamide 17 and aryl azide 23.
|
Displacement [3H]naloxone from rat-brain Opioid receptors
|
Rattus norvegicus
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Potential affinity labels for the opiate receptor based on fentanyl and related compounds.
Year : 1982
Volume : 25
Issue : 8
First Page : 913
Last Page : 919
Authors : Maryanoff BE, Simon EJ, Gioannini T, Gorissen H.
Abstract : Derivatives of fentanyl, 3-methylfentanyl, sufentanil, and lofentanil, possessing chemo- or photoaffinity functionalities, were synthesized as potential affinity reagents for the opiate receptor. Opiate receptor binding constants (IC50) were determined in competition experiments with [3H]naloxone and [3H]naltrexone. Affinity-labeling experiments were generally unsuccessful, although some irreversible attachment was achieved with alpha-diazoamide 17 and aryl azide 23.
|
In vitro affinity to displace [3H]naloxone from opiate receptor in freshly prepared rat brain homogenates
|
None
|
2.16
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of 4,4-disubstituted piperidines.
Year : 1989
Volume : 32
Issue : 5
First Page : 968
Last Page : 974
Authors : Colapret JA, Diamantidis G, Spencer HK, Spaulding TC, Rudo FG.
Abstract : A new class of piperidine derivatives is added to the increasing family of compounds related to fentanyl and carfentanil. Herein, we describe the synthesis and pharmacology of a number of 1-(arylethyl)-4-(acylamino)-4-[(acyloxy)-methyl]piperidines such as 9, 15, and 23. As expected, many of these congeners of fentanyl are extremely potent narcotic agonists. The aim of the study was to identify short-acting analgesic agents (i.e. less than 6 min in the mouse hot-plate assay) for possible use in the surgical theater. Many of the drugs proved to be of intermediate and long duration (i.e. 6-15 min and greater than 15 min, respectively). In addition to analgesic activity, many of the compounds exhibited anesthetic properties as well. The structure-activity relationship for these entities is presented and discussed.
|
Displacement of [3H]DAMGO (2 nM ) from opioid receptor mu 1 in human brain
|
Homo sapiens
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fentanyl derivatives bearing aliphatic alkaneguanidinium moieties: a new series of hybrid molecules with significant binding affinity for mu-opioid receptors and I2-imidazoline binding sites.
Year : 2004
Volume : 14
Issue : 2
First Page : 491
Last Page : 493
Authors : Dardonville C, Jagerovic N, Callado LF, Callado LF, Meana JJ.
Abstract : A new series of fentanyl derivatives [i.e., N-[1-(2-phenethyl)-4-piperidyl]-N-(guanidinoalkyl)propanamide] bearing aliphatic alkaneguanidinium moieties were prepared. Their affinities for the micro opioid receptors and for the I(2)-imidazoline binding sites (I(2)-IBS) were determined on human post-mortem prefrontal cortex membranes. All of these hybrid compounds had significant and/or very high affinity for both receptors in the nanomolar range, meaning an improvement compared to the prototype N-[1-(2-phenethyl)-4-piperidyl]-N-(guanidinopropyl)propanamide previously reported.
|
Binding affinity against Opioid receptor mu 1
|
None
|
3.97
nM
|
|
Journal : J. Med. Chem.
Title : Molecular docking reveals a novel binding site model for fentanyl at the mu-opioid receptor.
Year : 2000
Volume : 43
Issue : 3
First Page : 381
Last Page : 391
Authors : Subramanian G, Paterlini MG, Portoghese PS, Ferguson DM.
Abstract : The ligand binding modes of a series of fentanyl derivatives are examined using a combination of conformational analysis and molecular docking to the mu-opioid receptor. Condensed-phase molecular dynamics simulations are applied to evaluate potential relationships between ligand conformation and fentanyl substitution and to generate probable "bioactive" structures for the ligand series. Automated docking of the largely populated solution conformers identified a common binding site orientation that places the N-phenethyl group of fentanyl deep in a crevice between transmembrane (TM) helices II and III while the N-phenylpropanamide group projected toward a pocket formed by TM-III, -VI, and -VII domains. An analysis of the binding modes indicates the most potent fentanyl derivatives adopt an extended conformation both in solution and in the bound state, suggesting binding affinity may depend on the conformational preferences of the ligands. The results are consistent with ligand binding data derived from chimeric and mutant receptor studies as well as structure-activity relationship data reported on a wide range of fentanyl analogues. The binding site model is also compared to that of N-phenethylnormorphine. An overlay of the bound conformation of the opiate and cis-3-methylfentanyl shows the N-phenethyl groups occupy equivalent binding domains in the receptor. While the cationic amines of both ligand classes were found docked to an established anchor site (D149 in TM-III), no overlap was observed between the N-phenylpropanamide group and the remaining components of the opiate scaffold. The unique binding mode(s) proposed for the fentanyl series may, in part, explain the difficulties encountered in defining models of recognition at the mu-receptor and suggest opioid receptors may display multiple binding epitopes. Furthermore, the results provide new insight to the design of experiments aimed at understanding the structural basis to the differential selectivities of ligands at the mu-, delta-, and kappa-opioid receptors.
|
Ability to displace [3H]naloxone from the Opioid receptor mu 1 isolated from the rat brain membranes.
|
None
|
2.16
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of a series of new 3-methyl-1,4-disubstituted-piperidine analgesics.
Year : 1990
Volume : 33
Issue : 10
First Page : 2876
Last Page : 2882
Authors : Lalinde N, Moliterni J, Wright D, Spencer HK, Ossipov MH, Spaulding TC, Rudo FG.
Abstract : The synthesis and intravenous analgesic activity of a series of 3-methyl-4-(N-phenyl amido)piperidines, entries 34-79, is described. The methoxyacetamide pharmacophore produced a series of compounds with optimal analgesic potency and short duration of action. cis-42 was 13,036 times more potent than morphine and 29 times more potent than fentanyl; however, the corresponding diastereomer 43 was only 2778 and 6 times more potent, respectively. Compounds 40, 43, 47, and 57 are extremely short acting; all had durations of action of about 2 min, which was about 1/5 of that of fentanyl in the mouse hot-plate test at a dose equivalent to 2 times the ED50 analgesic dose. Among the many compounds that displayed exceptional analgesic activity, duration of action was one of the main factors for choosing a candidate for further pharmacological investigation. At present, cis-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-3-meth yl-4- [N-in equilibrium 2-fluorophenyl)methoxyacetamido]piperidine hydrochloride (40) (Anaquest, A-3331.HCl, Brifentanil) is in clinical evaluation. Opiate analgesics that possess short duration of action are excellent candidates for short surgical procedures in an outpatient setting where a rapid recovery is required.
|
Inhibition of [3H]DAMGO binding to mu opioid receptor of rat brain membranes
|
None
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors.
Year : 2003
Volume : 46
Issue : 4
First Page : 623
Last Page : 633
Authors : Bishop MJ, Garrido DM, Boswell GE, Collins MA, Harris PA, McNutt RW, O'Neill SJ, Wei K, Chang KJ.
Abstract : Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.
|
Binding affinity towards Opioid receptor mu 1 using [3H]DAMGO as radioligand.
|
None
|
3.97
nM
|
|
Journal : J. Med. Chem.
Title : Enantiomers of diastereomeric cis-N-[1-(2-hydroxy-2-phenylethyl)- 3-methyl-4-piperidyl]-N-phenylpropanamides: synthesis, X-ray analysis, and biological activities.
Year : 1995
Volume : 38
Issue : 9
First Page : 1547
Last Page : 1557
Authors : Brine GA, Stark PA, Liu Y, Carroll FI, Singh P, Xu H, Rothman RB.
Abstract : (+/-)-cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide (1) is a mixture of four stereoisomers [(2S,3R,4S)-1a, (2R,3R,4S)-1b, (2R,3S,4R)-1c, and (2S,3S,4R)-1d], which together constitute two diastereoisomeric pairs of optical isomers. These four stereoisomers were prepared from optically active intermediates of known absolute configuration by procedures which had no effect on the configurations of the piperidine 3- and 4-carbons. The configuration of the phenylethyl 2-carbon in the final products was determined by X-ray analysis of (2S,3S,4R)-1d. A 1H NMR comparison of the final products to ohmefentanyl established that the racemic pair previously known as ohmefentanyl was a mixture of (2S,3R,4S)-1a and (2R,3S,4R)-1c. The individual activities of 1a, 1b, 1c, and 1d were evaluated in a variety of binding and pharmacological assays. The binding data revealed that isomers 1b and 1c had the highest affinity and selectivity for the mu site labeled with [3H]DAMGO. In contrast, the four isomers displaced [3H]etorphine in the order 1a approximately 1b > 1c approximately 1d. Evaluation of the four isomers on the mouse vas deferens (MVD) preparation revealed a potency order of 1a > 1b > 1c > 1d with concentrations of 1a and 1b in the femtomolar range causing inhibition. Experiments using the antagonists naltrexone (mu), ICI 174864 (delta), and norbinaltorphimine (kappa) demonstrated that the effects of 1a were mediated largely by the mu receptor while both delta and kappa agonist effects contributed to the actions of 1b and 1c. Isomer 1d acted as a weak mu antagonist in the MVD preparation. The same potency order was observed in a mouse analgesic assay and a rhesus monkey single dose suppression study. From the latter study the potency of 1a was estimated to be 20,000-50,000 times that of morphine, making this isomer one of the most potent opiates known. In the rhesus monkey study, isomer 1d failed to substitute for morphine and seemed to exacerbate withdrawal at doses of 0.6, 3.0, and 6.0 mg/kg. On the basis of the mouse data, isomer 1a was 21,000 times more potent than 1d, whereas isomers 1b and 1c were similar in their opiate activity in vivo. Using the optical isomers of cis-3-methylfentanyl as reference compounds, we analyzed the effects on the pharmacological activities of introducing a phenylethyl 2-hydroxyl group into the molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
|
Displacement [3H]-naloxone from the Opioid receptor mu 1 isolated from rat brain membrane.
|
None
|
2.16
nM
|
|
Journal : J. Med. Chem.
Title : New 4-(heteroanilido)piperidines, structurally related to the pure opioid agonist fentanyl, with agonist and/or antagonist properties.
Year : 1989
Volume : 32
Issue : 3
First Page : 663
Last Page : 671
Authors : Bagley JR, Wynn RL, Rudo FG, Doorley BM, Spencer HK, Spaulding T.
Abstract : A research program based on certain heterocyclic modifications (12-50) of the fentanyl (1) molecule has generated a novel class of opioids. In the mouse hot-plate test, these compounds were weaker analgesics than 1. Two types of antagonists were observed in morphine-treated rabbits: those (e.g., 28) that reversed both respiratory depression and analgesia and those (e.g. 32) that selectively reversed respiratory depression. Evaluation of in vitro binding affinities to rat brain opioid receptors was inconclusive for a common locus of action for the agonist as well as the antagonist component. Further pharmacological evaluation of 32, N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide, in the rat showed it to be a potent analgesic (ED50 = 0.07 mg/kg, tail-flick test) with little cardiovascular and respiratory depression when compared to fentanyl.
|
Binding affinity against mu-opiate receptor (human) using [3H]DAMGO radioligand
|
None
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.
Year : 2001
Volume : 44
Issue : 21
First Page : 3378
Last Page : 3390
Authors : Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Déprez B.
Abstract : Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.
|
Binding affinity against mu opioid receptor in guinea pig brain membranes
|
Cavia porcellus
|
8.45
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models.
Year : 1998
Volume : 8
Issue : 19
First Page : 2685
Last Page : 2688
Authors : Wang C, McFadyen IJ, Traynor JR, Mosberg HI.
Abstract : A pair of diastereomeric peptidomimetics based upon opioid receptor-binding pharmacophore models derived for a series of opioid tetrapeptides was synthesized. Both analogues display high opioid receptor affinity, moderate selectivity for the mu opioid receptor, and are potent, full agonists.
|
Compound was tested for its ability to stimulate [35S]GTP-gamma-S, binding to membranes from C6 glioma cells stably expressing rat mu opioid receptor
|
None
|
32.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models.
Year : 1998
Volume : 8
Issue : 19
First Page : 2685
Last Page : 2688
Authors : Wang C, McFadyen IJ, Traynor JR, Mosberg HI.
Abstract : A pair of diastereomeric peptidomimetics based upon opioid receptor-binding pharmacophore models derived for a series of opioid tetrapeptides was synthesized. Both analogues display high opioid receptor affinity, moderate selectivity for the mu opioid receptor, and are potent, full agonists.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
73.6
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Agonist activity at mu opioid receptor in guinea pig ileum assessed as inhibition of electrically-stimulated muscle contraction
|
Cavia porcellus
|
3.45
nM
|
|
Journal : J. Med. Chem.
Title : "Carba"-analogues of fentanyl are opioid receptor agonists.
Year : 2010
Volume : 53
Issue : 7
First Page : 2875
Last Page : 2881
Authors : Weltrowska G, Chung NN, Lemieux C, Guo J, Lu Y, Wilkes BC, Schiller PW.
Abstract : There is evidence to indicate that the Asp residue in the third transmembrane helix (TMH) of opioid receptors forms a salt bridge with the positively charged nitrogen of endogenous and exogenous opioid ligands. To further examine the role of this electrostatic interaction in receptor binding and activation, we synthesized "carba"-analogues of a published fentanyl analogue containing a 3-(guanidinomethyl)-benzyl group in place of the phenyl moiety attached to the ethylamido group (C. Dardonville et al., Bioorg. Med. Chem. 2006, 14, 6570-6580 (1)), in which the piperidine ring nitrogen was replaced with a carbon. As expected, the resulting cis and trans isomers (8a and 8b) showed reduced mu and kappa opioid receptor binding affinities as compared to 1 but, surprisingly, retained opioid full agonist activity with about half the potency of leucine-enkephalin in the guinea pig ileum assay. In conjunction with performed receptor docking studies, these results indicate that the electrostatic interaction of the protonated nitrogen in the piperidine ring of fentanyl analogues with the Asp residue in the third TMH is not a conditio sine qua non for opioid receptor activation.
|
Agonist activity at delta opioid receptor in mouse vas deferens assessed as inhibition of electrically-stimulated muscle contraction
|
Mus musculus
|
9.45
nM
|
|
Journal : J. Med. Chem.
Title : "Carba"-analogues of fentanyl are opioid receptor agonists.
Year : 2010
Volume : 53
Issue : 7
First Page : 2875
Last Page : 2881
Authors : Weltrowska G, Chung NN, Lemieux C, Guo J, Lu Y, Wilkes BC, Schiller PW.
Abstract : There is evidence to indicate that the Asp residue in the third transmembrane helix (TMH) of opioid receptors forms a salt bridge with the positively charged nitrogen of endogenous and exogenous opioid ligands. To further examine the role of this electrostatic interaction in receptor binding and activation, we synthesized "carba"-analogues of a published fentanyl analogue containing a 3-(guanidinomethyl)-benzyl group in place of the phenyl moiety attached to the ethylamido group (C. Dardonville et al., Bioorg. Med. Chem. 2006, 14, 6570-6580 (1)), in which the piperidine ring nitrogen was replaced with a carbon. As expected, the resulting cis and trans isomers (8a and 8b) showed reduced mu and kappa opioid receptor binding affinities as compared to 1 but, surprisingly, retained opioid full agonist activity with about half the potency of leucine-enkephalin in the guinea pig ileum assay. In conjunction with performed receptor docking studies, these results indicate that the electrostatic interaction of the protonated nitrogen in the piperidine ring of fentanyl analogues with the Asp residue in the third TMH is not a conditio sine qua non for opioid receptor activation.
|
Displacement of [3H]DAMGO from mu opioid receptor in rat brain membrane
|
Rattus norvegicus
|
5.9
nM
|
|
Journal : J. Med. Chem.
Title : "Carba"-analogues of fentanyl are opioid receptor agonists.
Year : 2010
Volume : 53
Issue : 7
First Page : 2875
Last Page : 2881
Authors : Weltrowska G, Chung NN, Lemieux C, Guo J, Lu Y, Wilkes BC, Schiller PW.
Abstract : There is evidence to indicate that the Asp residue in the third transmembrane helix (TMH) of opioid receptors forms a salt bridge with the positively charged nitrogen of endogenous and exogenous opioid ligands. To further examine the role of this electrostatic interaction in receptor binding and activation, we synthesized "carba"-analogues of a published fentanyl analogue containing a 3-(guanidinomethyl)-benzyl group in place of the phenyl moiety attached to the ethylamido group (C. Dardonville et al., Bioorg. Med. Chem. 2006, 14, 6570-6580 (1)), in which the piperidine ring nitrogen was replaced with a carbon. As expected, the resulting cis and trans isomers (8a and 8b) showed reduced mu and kappa opioid receptor binding affinities as compared to 1 but, surprisingly, retained opioid full agonist activity with about half the potency of leucine-enkephalin in the guinea pig ileum assay. In conjunction with performed receptor docking studies, these results indicate that the electrostatic interaction of the protonated nitrogen in the piperidine ring of fentanyl analogues with the Asp residue in the third TMH is not a conditio sine qua non for opioid receptor activation.
|
Displacement of [3H]DSLET from delta opioid receptor in rat brain membrane
|
Rattus norvegicus
|
568.0
nM
|
|
Journal : J. Med. Chem.
Title : "Carba"-analogues of fentanyl are opioid receptor agonists.
Year : 2010
Volume : 53
Issue : 7
First Page : 2875
Last Page : 2881
Authors : Weltrowska G, Chung NN, Lemieux C, Guo J, Lu Y, Wilkes BC, Schiller PW.
Abstract : There is evidence to indicate that the Asp residue in the third transmembrane helix (TMH) of opioid receptors forms a salt bridge with the positively charged nitrogen of endogenous and exogenous opioid ligands. To further examine the role of this electrostatic interaction in receptor binding and activation, we synthesized "carba"-analogues of a published fentanyl analogue containing a 3-(guanidinomethyl)-benzyl group in place of the phenyl moiety attached to the ethylamido group (C. Dardonville et al., Bioorg. Med. Chem. 2006, 14, 6570-6580 (1)), in which the piperidine ring nitrogen was replaced with a carbon. As expected, the resulting cis and trans isomers (8a and 8b) showed reduced mu and kappa opioid receptor binding affinities as compared to 1 but, surprisingly, retained opioid full agonist activity with about half the potency of leucine-enkephalin in the guinea pig ileum assay. In conjunction with performed receptor docking studies, these results indicate that the electrostatic interaction of the protonated nitrogen in the piperidine ring of fentanyl analogues with the Asp residue in the third TMH is not a conditio sine qua non for opioid receptor activation.
|
Displacement of [3H]U69593 from kappa opioid receptor in guinea pig brain membrane
|
Cavia porcellus
|
298.0
nM
|
|
Journal : J. Med. Chem.
Title : "Carba"-analogues of fentanyl are opioid receptor agonists.
Year : 2010
Volume : 53
Issue : 7
First Page : 2875
Last Page : 2881
Authors : Weltrowska G, Chung NN, Lemieux C, Guo J, Lu Y, Wilkes BC, Schiller PW.
Abstract : There is evidence to indicate that the Asp residue in the third transmembrane helix (TMH) of opioid receptors forms a salt bridge with the positively charged nitrogen of endogenous and exogenous opioid ligands. To further examine the role of this electrostatic interaction in receptor binding and activation, we synthesized "carba"-analogues of a published fentanyl analogue containing a 3-(guanidinomethyl)-benzyl group in place of the phenyl moiety attached to the ethylamido group (C. Dardonville et al., Bioorg. Med. Chem. 2006, 14, 6570-6580 (1)), in which the piperidine ring nitrogen was replaced with a carbon. As expected, the resulting cis and trans isomers (8a and 8b) showed reduced mu and kappa opioid receptor binding affinities as compared to 1 but, surprisingly, retained opioid full agonist activity with about half the potency of leucine-enkephalin in the guinea pig ileum assay. In conjunction with performed receptor docking studies, these results indicate that the electrostatic interaction of the protonated nitrogen in the piperidine ring of fentanyl analogues with the Asp residue in the third TMH is not a conditio sine qua non for opioid receptor activation.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
-53.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
22.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
11.7
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Analgesic activity in ip dosed Swiss albino Mus musculus (mouse) assessed as decrease in time spent in formalin-induced paw licking administered 30 min prior to formalin injection measured after 15 to 30 min (late phase)
|
Mus musculus
|
78.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice
Year : 2013
Volume : 22
Issue : 8
First Page : 3888
Last Page : 3896
Authors : Gupta PK, Yadav SK, Bhutia YD, Singh P, Rao P, Gujar NL, Ganesan K, Bhattacharya R
|
Inhibition of delta opioid receptor in mouse vas deferens assessed as inhibition of electrically-stimulated muscle contraction
|
Mus musculus
|
9.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Effect of anchoring 4-anilidopiperidines to opioid peptides.
Year : 2013
Volume : 23
Issue : 11
First Page : 3434
Last Page : 3437
Authors : Petrov RR, Lee YS, Vardanyan RS, Liu L, Ma SW, Davis P, Lai J, Porreca F, Vanderah TW, Hruby VJ.
Abstract : We report here the design, synthesis, and in vitro characterization of new opioid peptides featuring a 4-anilidopiperidine moiety. Despite the fact that the chemical structures of fentanyl surrogates have been found suboptimal per se for the opioid activity, the corresponding conjugates with opioid peptides displayed potent opioid activity. These studies shed an instructive light on the strategies and potential therapeutic values of anchoring the 4-anilidopiperidine scaffold to different classes of opioid peptides.
|
Inhibition of mu opioid receptor in guinea pig ileum assessed as inhibition of electrically-stimulated muscle contraction
|
Cavia porcellus
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Effect of anchoring 4-anilidopiperidines to opioid peptides.
Year : 2013
Volume : 23
Issue : 11
First Page : 3434
Last Page : 3437
Authors : Petrov RR, Lee YS, Vardanyan RS, Liu L, Ma SW, Davis P, Lai J, Porreca F, Vanderah TW, Hruby VJ.
Abstract : We report here the design, synthesis, and in vitro characterization of new opioid peptides featuring a 4-anilidopiperidine moiety. Despite the fact that the chemical structures of fentanyl surrogates have been found suboptimal per se for the opioid activity, the corresponding conjugates with opioid peptides displayed potent opioid activity. These studies shed an instructive light on the strategies and potential therapeutic values of anchoring the 4-anilidopiperidine scaffold to different classes of opioid peptides.
|
Displacement of [3H]-DAMGO from Swiss Webster mouse neural membranes mu opioid receptor after 60 mins by liquid scintillation spectrometric analysis
|
Mus musculus
|
5.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.
Year : 2015
Volume : 23
Issue : 18
First Page : 6185
Last Page : 6194
Authors : Deekonda S, Wugalter L, Kulkarni V, Rankin D, Largent-Milnes TM, Davis P, Bassirirad NM, Lai J, Vanderah TW, Porreca F, Hruby VJ.
Abstract : A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.
|
Displacement of [3H]-DPDPE from Swiss Webster mouse neural membranes delta opioid receptor after 60 mins by liquid scintillation spectrometric analysis
|
Mus musculus
|
568.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.
Year : 2015
Volume : 23
Issue : 18
First Page : 6185
Last Page : 6194
Authors : Deekonda S, Wugalter L, Kulkarni V, Rankin D, Largent-Milnes TM, Davis P, Bassirirad NM, Lai J, Vanderah TW, Porreca F, Hruby VJ.
Abstract : A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.
|
Agonist activity at delta opioid receptor in beta-funaltrexamine-treated mouse vas deferens
|
Mus musculus
|
3.45
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.
Year : 2015
Volume : 23
Issue : 18
First Page : 6185
Last Page : 6194
Authors : Deekonda S, Wugalter L, Kulkarni V, Rankin D, Largent-Milnes TM, Davis P, Bassirirad NM, Lai J, Vanderah TW, Porreca F, Hruby VJ.
Abstract : A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.
|
Agonist activity at mu opioid receptor in beta-funaltrexamine-treated guinea pig isolated ileum
|
Cavia porcellus
|
9.45
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.
Year : 2015
Volume : 23
Issue : 18
First Page : 6185
Last Page : 6194
Authors : Deekonda S, Wugalter L, Kulkarni V, Rankin D, Largent-Milnes TM, Davis P, Bassirirad NM, Lai J, Vanderah TW, Porreca F, Hruby VJ.
Abstract : A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.
|
Displacement of [3H] DAMGO from rat mu-opioid receptor
|
Rattus norvegicus
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.
Year : 2015
Volume : 25
Issue : 20
First Page : 4683
Last Page : 4688
Authors : Deekonda S, Wugalter L, Rankin D, Largent-Milnes TM, Davis P, Wang Y, Bassirirad NM, Lai J, Kulkarni V, Vanderah TW, Porreca F, Hruby VJ.
Abstract : We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.
|
Agonist activity at delta opioid receptor in mouse vas deferens assessed as inhibition of electrically stimulated muscle contraction
|
Mus musculus
|
9.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.
Year : 2015
Volume : 25
Issue : 20
First Page : 4683
Last Page : 4688
Authors : Deekonda S, Wugalter L, Rankin D, Largent-Milnes TM, Davis P, Wang Y, Bassirirad NM, Lai J, Kulkarni V, Vanderah TW, Porreca F, Hruby VJ.
Abstract : We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.
|
Agonist activity at mu opioid receptor in guinea pig ileum assessed as inhibition of electrically stimulated muscle contraction
|
Cavia porcellus
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.
Year : 2015
Volume : 25
Issue : 20
First Page : 4683
Last Page : 4688
Authors : Deekonda S, Wugalter L, Rankin D, Largent-Milnes TM, Davis P, Wang Y, Bassirirad NM, Lai J, Kulkarni V, Vanderah TW, Porreca F, Hruby VJ.
Abstract : We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.
|
Displacement of [3H]DPDPE from human delta opioid receptor
|
Homo sapiens
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.
Year : 2016
Volume : 24
Issue : 2
First Page : 85
Last Page : 91
Authors : Deekonda S, Rankin D, Davis P, Lai J, Vanderah TW, Porecca F, Hruby VJ.
Abstract : Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results.
|
Displacement of [3H]DAMGO from mu opioid receptor in rat brain membranes
|
Rattus norvegicus
|
5.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.
Year : 2016
Volume : 24
Issue : 2
First Page : 85
Last Page : 91
Authors : Deekonda S, Rankin D, Davis P, Lai J, Vanderah TW, Porecca F, Hruby VJ.
Abstract : Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results.
|
Agonist activity at Gi-coupled mu opioid receptor (unknown origin) expressed in HEK293T cells assessed as inhibition of cAMP production at pH 7.4 measured after 15 mins by Glo-Sensor assay
|
Homo sapiens
|
10.72
nM
|
|
Journal : ACS Med Chem Lett
Title : β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists.
Year : 2019
Volume : 10
Issue : 9
First Page : 1353
Last Page : 1356
Authors : Rosas R, Huang XP, Roth BL, Dockendorff C.
Abstract : The concept recently postulated by Stein and co-workers (<i>Science</i> <b>2017</b>, <i>355</i>, 966) that mu opioid receptor (MOR) agonists possessing amines with attenuated basicity show pH-dependent activity and can selectively act at damaged, low pH tissues has been additionally supported by in vitro studies reported here. We synthesized and tested analogs of fentanyl possessing one or two fluorine atoms at the beta position of the phenethylamine side chain, with additional fluorines optionally added to the benzene ring of the side chain. These compounds were synthesized in 1 to 3 steps from commercial building blocks. The novel bis-fluorinated analog RR-49 showed superior pH sensitivity, with full efficacy relative to DAMGO, but with 19-fold higher potency (IC<sub>50</sub>) in a MOR cAMP assay at pH 6.5 versus 7.4. Such compounds hold significant promise as analgesics for inflammatory pain with reduced abuse potential.
|
Agonist activity at Gi-coupled mu opioid receptor (unknown origin) expressed in HEK293T cells assessed as inhibition of cAMP production at pH 6.5 measured after 15 mins by Glo-Sensor assay
|
Homo sapiens
|
5.495
nM
|
|
Journal : ACS Med Chem Lett
Title : β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists.
Year : 2019
Volume : 10
Issue : 9
First Page : 1353
Last Page : 1356
Authors : Rosas R, Huang XP, Roth BL, Dockendorff C.
Abstract : The concept recently postulated by Stein and co-workers (<i>Science</i> <b>2017</b>, <i>355</i>, 966) that mu opioid receptor (MOR) agonists possessing amines with attenuated basicity show pH-dependent activity and can selectively act at damaged, low pH tissues has been additionally supported by in vitro studies reported here. We synthesized and tested analogs of fentanyl possessing one or two fluorine atoms at the beta position of the phenethylamine side chain, with additional fluorines optionally added to the benzene ring of the side chain. These compounds were synthesized in 1 to 3 steps from commercial building blocks. The novel bis-fluorinated analog RR-49 showed superior pH sensitivity, with full efficacy relative to DAMGO, but with 19-fold higher potency (IC<sub>50</sub>) in a MOR cAMP assay at pH 6.5 versus 7.4. Such compounds hold significant promise as analgesics for inflammatory pain with reduced abuse potential.
|
Binding affinity to mu opioid receptor (unknown origin) expressed in HEK cells at pH 7.4
|
Homo sapiens
|
1.1
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Agonist activity at human mu opioid receptor expressed in CHO cell membranes after 1 hr by [35S]-GTPgammaS binding assay
|
Homo sapiens
|
43.0
nM
|
|
Journal : J Med Chem
Title : Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential.
Year : 2018
Volume : 61
Issue : 22
First Page : 9841
Last Page : 9878
Authors : Tan L, Yan W, McCorvy JD, Cheng J.
Abstract : G protein-coupled receptors (GPCRs) signal through both G-protein-dependent and G-protein-independent pathways, and β-arrestin recruitment is the most recognized one of the latter. Biased ligands selective for either pathway are expected to regulate biological functions of GPCRs in a more precise way, therefore providing new drug molecules with superior efficacy and/or reduced side effects. During the past decade, biased ligands have been discovered and developed for many GPCRs, such as the μ opioid receptor, the angiotensin II receptor type 1, the dopamine D2 receptor, and many others. In this Perspective, recent advances in this field are reviewed by discussing the structure-functional selectivity relationships (SFSRs) of GPCR biased ligands and the therapeutic potential of these molecules. Further understanding of the biological functions associated with each signaling pathway and structural basis for biased signaling will facilitate future drug design in this field.
|
Agonist activity at human mu opioid receptor expressed in human U2OS cells co-transfected with beta-arrestin-2 assessed as increase in beta-arrestin-2 recruitment after 90 mins by BRET assay
|
Homo sapiens
|
53.0
nM
|
|
Journal : J Med Chem
Title : Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential.
Year : 2018
Volume : 61
Issue : 22
First Page : 9841
Last Page : 9878
Authors : Tan L, Yan W, McCorvy JD, Cheng J.
Abstract : G protein-coupled receptors (GPCRs) signal through both G-protein-dependent and G-protein-independent pathways, and β-arrestin recruitment is the most recognized one of the latter. Biased ligands selective for either pathway are expected to regulate biological functions of GPCRs in a more precise way, therefore providing new drug molecules with superior efficacy and/or reduced side effects. During the past decade, biased ligands have been discovered and developed for many GPCRs, such as the μ opioid receptor, the angiotensin II receptor type 1, the dopamine D2 receptor, and many others. In this Perspective, recent advances in this field are reviewed by discussing the structure-functional selectivity relationships (SFSRs) of GPCR biased ligands and the therapeutic potential of these molecules. Further understanding of the biological functions associated with each signaling pathway and structural basis for biased signaling will facilitate future drug design in this field.
|
Displacement of [3H]PPP from sigma1 receptor (unknown origin)
|
Homo sapiens
|
354.0
nM
|
|
Journal : MedChemComm
Title : Affinity of fentanyl and its derivatives for the σ<sub>1</sub>-receptor.
Year : 2019
Volume : 10
Issue : 7
First Page : 1187
Last Page : 1191
Authors : Lipiński PFJ, Szűcs E, Jarończyk M, Kosson P, Benyhe S, Misicka A, Dobrowolski JC, Sadlej J.
Abstract : Fentanyl and its 11 commercially available derivatives were investigated as to their affinity for the σ<sub>1</sub> receptor. The parent compound is a rather poor binder (IC<sub>50</sub> = 4973 nM), but its close derivatives (benzylfentanyl or <i>p</i>-fluorofentanyl) have submicromolar affinities. Modelling provides a structural basis for the observed trends in activity.
|
Displacement of [3H]DAMGO from rat brain mu opioid receptor incubated for 60 mins by microbeta scintillation counting method
|
Rattus norvegicus
|
1.23
nM
|
|
Journal : MedChemComm
Title : Affinity of fentanyl and its derivatives for the σ<sub>1</sub>-receptor.
Year : 2019
Volume : 10
Issue : 7
First Page : 1187
Last Page : 1191
Authors : Lipiński PFJ, Szűcs E, Jarończyk M, Kosson P, Benyhe S, Misicka A, Dobrowolski JC, Sadlej J.
Abstract : Fentanyl and its 11 commercially available derivatives were investigated as to their affinity for the σ<sub>1</sub> receptor. The parent compound is a rather poor binder (IC<sub>50</sub> = 4973 nM), but its close derivatives (benzylfentanyl or <i>p</i>-fluorofentanyl) have submicromolar affinities. Modelling provides a structural basis for the observed trends in activity.
|
Agonist activity at human MOR expressed in CHO-K1 cells assessed as cAMP accumulation incubated for 30 mins and measured after 1 hr by Eu-cAMP tracer based TR-FRET assay
|
Homo sapiens
|
0.51
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis and μ-Opioid Activity of the Primary Metabolites of Carfentanil.
Year : 2019
Volume : 10
Issue : 11
First Page : 1568
Last Page : 1572
Authors : Hsu FL, Walz AJ, Myslinski JM, Kong L, Feasel MG, Goralski TDP, Rose T, Cooper NJ, Roughley N, Timperley CM.
Abstract : Carfentanil is a synthetic opioid significantly more potent than clinically prescribed fentanyl. The primary metabolites of carfentanil, generated from human liver microsomes, were structurally confirmed through chemical synthesis. The synthesized compounds were evaluated for μ-opioid receptor (MOR) functional activity. Of the six metabolites assayed, a major metabolite showed comparable activity to the parent opioid. Three other metabolites showed significant MOR functional activity. The availability of the metabolites could aid improvements in the analysis of biomedical samples obtained from suspected human exposures to carfentanil and development of treatment protocols.
|
Agonist activity at mu opioid receptor (unknown origin) expressed in HEK293-A cells assessed as inhibition of forskolin-stimulated cAMP accumulation incubated for 30 mins by competition PKA binding assay
|
Homo sapiens
|
17.2
nM
|
|
Agonist activity at mu opioid receptor (unknown origin) expressed in HEK293-A cells assessed as inhibition of forskolin-stimulated cAMP accumulation incubated for 30 mins by competition PKA binding assay
|
Homo sapiens
|
17.38
nM
|
|
Journal : J Med Chem
Title : Synthesis and Biological Characterization of Cyclic Disulfide-Containing Peptide Analogs of the Multifunctional Opioid/Neuropeptide FF Receptor Agonists That Produce Long-Lasting and Nontolerant Antinociception.
Year : 2020
Volume : 63
Issue : 24
First Page : 15709
Last Page : 15725
Authors : Zhang M,Xu B,Li N,Liu H,Shi X,Zhang Q,Shi Y,Xu K,Xiao J,Chen D,Zhu H,Sun Y,Zhang T,Zhang R,Fang Q
Abstract : In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent μ-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.
|
Inhibition of sigma 1 receptor (unknown origin)
|
Homo sapiens
|
0.39
nM
|
|
Journal : Eur J Med Chem
Title : Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain.
Year : 2020
Volume : 191
First Page : 112144
Last Page : 112144
Authors : Xiong J,Jin J,Gao L,Hao C,Liu X,Liu BF,Chen Y,Zhang G
Abstract : We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ receptor (K σ = 1.86 nM) and μ receptor (K μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ/μ receptor profiles, may be a potential candidate for treating neuropathic pain.
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Displacement of [3H]DAMGO from human mu opioid receptor expressed in HEK293 cell membrane incubated for 60 mins by radioligand binding assay
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Homo sapiens
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5.23
nM
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Displacement of [3H]-N-methylspiperone from human dopamine D4 receptor expressed in HEK293 cell membranes incubated for 60 mins by microbeta scintillation counting analysis
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Homo sapiens
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554.0
nM
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