|
Compound was evaluated for the inhibition of [3H]WIN-55212-2 binding in rat cerebellum membranes
|
None
|
5.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : C-Attached aminoalkylindoles: potent cannabinoid mimetics
Year : 1996
Volume : 6
Issue : 1
First Page : 17
Last Page : 22
Authors : D'Ambra TE, Eissenstat MA, Abt J, Ackerman JH, Bacon ER, Bell MR, Carabateas PM, Josef KA, Kumar V, Weaver JD, Arnold R, Casiano FM, Chippari SM, Haycock DA, Kuster JE, Luttinger DA, Stevenson JI, Ward SJ, Hill W, Khanolkar A, Makriyannis A
|
The compound was tested in vitro for binding activity against THC cannabinoid receptor site, using 3H-CP-55940 as the radioligand
|
None
|
218.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of ether and related analogues of delta 8-, delta 9-, and delta 9,11-tetrahydrocannabinol.
Year : 1991
Volume : 34
Issue : 11
First Page : 3310
Last Page : 3316
Authors : Compton DR, Prescott WR, Martin BR, Siegel C, Gordon PM, Razdan RK.
Abstract : The primary goal of this research was to synthesize a series of ether analogues of the cannabinoid drug class and to evaluate their agonist and antagonist pharmacological properties in either the mouse or the rat. Agonist and antagonist activity was evaluated in mice using a multiple-evaluation procedure (locomotor activity, tail-flick latency, hypothermia, ring immobility) and activity in rats determined in a discriminative stimulus paradigm. Additionally, novel analogues were evaluated for their ability to bind to the THC receptor site labeled by 3H-CP-55,940. None of the cannabinoid analogues were capable of attenuating the effects of delta 9-THC (3 mg/kg) in either the rat (doses up to 10 mg/kg) or in the mouse (doses up to 30 mg/kg). It also appears that the compounds with minimal in vivo activity are not mixed agonist/antagonists. These data would suggest that the phenolic hydroxyl is important for receptor recognition (binding) and in vivo potency. Additionally, cannabinoid methyl ethers previously considered inactive have been found to produce limited activity. Lastly, data suggest that delta 9,11-THC is more potent than previous reports indicated, and does possess pharmacological activity.
|
Compound was evaluated for the competitive inhibition of [3H]3-(1,1-Dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol to cannabinoid receptor from synaptosomal membranes of rat whole brain
|
None
|
46.0
nM
|
|
Journal : J. Med. Chem.
Title : A novel probe for the cannabinoid receptor.
Year : 1992
Volume : 35
Issue : 11
First Page : 2065
Last Page : 2069
Authors : Devane WA, Breuer A, Sheskin T, Järbe TU, Eisen MS, Mechoulam R.
Abstract : The 1,1-dimethylheptyl (DMH) homologue of 7-hydroxy-delta 6-tetrahydrocannabinol (3) is the most potent cannabimimetic substance reported so far. Hydrogenation of 3 leads to a mixture of the epimers of 5'-(1,1-dimethylheptyl)-7-hydroxyhexahydrocannabinol or to either the equatorial (7) or to the axial epimer (8), depending on the catalysts and conditions used. Compound 7 discriminates for delta 1-THC (2) in pigeons (ED50 = 0.002 mg/kg, after 4.5 h), at the potency level of 3, and binds to the cannabinoid receptor with a KD of 45 pM, considerably lower than the Ki of 180 pM measured for compound 3 and the Ki of 2.0 nM measured for CP-55940 (1), a widely employed ligand. Tritiated 7 was used as a novel probe for the cannabinoid receptor.
|
Binding affinity was determined in vitro against cannabinoid receptor by ability to displace [3H]CP-55940
|
None
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, Synthesis and Pharmacology of Cannabimimetic Indoles
Year : 1994
Volume : 4
Issue : 4
First Page : 563
Last Page : 566
Authors : Huffman JW, Dai D, Martin BR, Compton DR
|
Binding affinity towards Cannabinoid receptor 1 using CP-55940 as radioligand in HEK293 EBNA cells
|
None
|
28.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids.
Year : 2003
Volume : 13
Issue : 20
First Page : 3487
Last Page : 3490
Authors : Krishnamurthy M, Ferreira AM, Moore BM.
Abstract : A series of novel phenyl substituted side-chain analogues of classical cannabinoids were synthesized and their CB1 and CB2 binding affinities were evaluated relative to Delta(8)-THC and compound 2. CB1 and CB2 binding assays indicate that the dimethyl and ketone analogues (3) and (6) display selectivity for the CB2 receptor in comparison to delta(8)-THC and compound 2. This study provides newer insights into the geometrical and functional group requirements of the ligand binding pockets of the CB1 and the CB2 receptors.
|
Binding affinity was determined for Cannabinoid receptor 1
|
None
|
41.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel cannabinol probes for CB1 and CB2 cannabinoid receptors.
Year : 2000
Volume : 43
Issue : 20
First Page : 3778
Last Page : 3785
Authors : Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK.
Abstract : The observation that the phenolic hydroxyl of THCs was important for binding to the CB1 receptor but not as critical for binding to the CB2 receptor prompted us to extend this finding to the cannabinol (CBN) series. To study the SAR of CBN analogues, CBN derivatives with substitution at the C-1, C-3, and C-9 positions were chosen since these positions have played a key role in the SAR of THCs. CBN-3-(1',1'-dimethylheptyl) analogues were prepared by sulfur dehydrogenation of Delta(8)-THC-3-(1',1'-dimethylheptyl) analogues. 9-Substituted CBN analogues were prepared by the standard sulfur dehydrogenation of 9-substituted Delta(8)-THC analogues (Scheme 1), which in turn were prepared following our previous procedure using selenium dioxide oxidation of the corresponding Delta(8)-THCs followed by sodium chlorite oxidation to give the 9-carboxy-Delta(8)-THC derivatives. 11-Hydroxy-CBN analogues were prepared from the corresponding 9-carbomethoxy-CBN analogues by reduction with LiAlH(4). Deoxy-CBN analogue 14 was prepared from the corresponding Delta(8)-THC analogue 11 by conversion of the phenolic hydroxyl to the phosphate derivative 12, followed by lithium ammonia reduction to provide the deoxy-Delta(8)-THC analogue 13, which in turn was dehydrogenated with sulfur to provide the deoxy-CBN analogue 14 (Scheme 2). The various analogues were assayed for binding both to the brain and the peripheral cannabinoid receptors (CB1 and CB2). We have found that the binding profile differs widely between the CBN and the THC series. Specifically, in the CBN series the removal of the phenolic hydroxyl decreases binding affinity to both the CB1 and CB2 receptors, whereas in the THC series, CB1 affinity is selectively reduced. Thus, in the CBN series, the selectivity of binding observed with the removal of the hydroxy group is decreased severalfold as compared to what occurs in the THC series. Generally, high affinity for the CB2 receptor was found in analogues when the phenolic hydroxyl was present. The 3-(1', 1'-dimethylheptyl) derivatives were found to have much higher affinities than the CBN analogues, which is in complete agreement with previously reported work by Rhee et al.
|
Binding affinity for Cannabinoid receptor 1 in absence of phenylmethylsulfonyl fluoride (PMSF)
|
None
|
41.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent anandamide analogs: the effect of changing the length and branching of the end pentyl chain.
Year : 1997
Volume : 40
Issue : 22
First Page : 3617
Last Page : 3625
Authors : Ryan WJ, Banner WK, Wiley JL, Martin BR, Razdan RK.
Abstract : To examine the effect of changing the length and branching of the end pentyl chain (C5H11) of anandamide (AN), various analogs 1a-h and 2a-f were synthesized from either the known aldehyde ester 6a or from the alcohol 6b and tested for their pharmacological activity. A reproducible procedure was developed for the conversion of arachidonic acid to 6a or 6b in gram quantities (overall yield 15%). The appropriate tetraene esters 7 were prepared by carrying out a Witting reaction, between 6a and the ylide generated from the phosphonium salt of the appropriate alkyl halide or between the ylide of 6d (prepared from 6a-->6b-->6c-->6d) and the appropriate alkyl aldehydes. They were then hydrolyzed to the corresponding acids and transformed into AN analogs 1 via their acid chlorides then treated with excess ethanolamine. alpha-Alkylation of esters 7 gave compounds 8 which were hydrolyzed to the corresponding acids. These acids via their acid chlorides and subsequent treatment with excess fluoroethylamine gave the target compounds 2. In this way analogs 1e and 2a-c were synthesized from 6d while all the remaining analogs were prepared from 6a. In order to assess the optimal length of the alkyl terminus, analogs 1a-d were prepared and showed moderately high affinities (18-55 nM). However analogs 1a-c failed to produce significant pharmacological effects at doses up to 30 mg/kg. Analog 1d was found to be a weak partial agonist. The reason for the lack of activity in 1a-c is presently not clear. Like the THCs, the branching of the end pentyl chain in AN (1e-h) increased potency both in in vitro and in vivo activities; the dimethylheptyl (DMH) analog 1e was the most potent in the series. Similar alkyl substitutions were carried out in the fluoro-2-methylanandamide series (2a-f), and all of these analogs had high receptor affinities (1-14 nM), the DMH analog 2a being the most potent. With a few exceptions they showed robust pharmacological effects, and AN-like profiles. It was shown that the SAR of the end pentyl chain in AN is very similar to that of THCs. However, the magnitude of enhanced potency observed when the side chain of THC was changed from straight to branched was not observed when the end chain of AN was similarly changed.
|
Effective concentration for inhibition of Cannabinoid receptor 1-mediated adenylyl cyclase activity using African green monkey (COS-7) cells transfected with the cDNA of rat CB1 receptor
|
None
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase.
Year : 1997
Volume : 40
Issue : 20
First Page : 3228
Last Page : 3233
Authors : Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R.
Abstract : Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB1 and CB2 (Ki values of 38.0 +/- 7.2 and 26.6 +/- 5.5 nM, respectively) and to inhibit CB1-mediated adenylylcyclase with an EC50 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).
|
Concentration of compound required to inhibit 50% of [3H]WIN-55212 binding to Cannabinoid receptor 1 in rat cerebellum membranes.
|
None
|
5.8
nM
|
|
Journal : J. Med. Chem.
Title : Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics.
Year : 1995
Volume : 38
Issue : 16
First Page : 3094
Last Page : 3105
Authors : Eissenstat MA, Bell MR, D'Ambra TE, Alexander EJ, Daum SJ, Ackerman JH, Gruett MD, Kumar V, Estep KG, Olefirowicz EM.
Abstract : Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands. In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of [3H]Win 55212-2 (5). Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists. The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position. A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist. Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids. The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors make sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid. Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).
|
Binding affinity for Cannabinoid receptor 1 using African green monkey (COS-7) cells transfected with the cDNA of rat brain synaptosomal membrane preparations.
|
None
|
66.5
nM
|
|
Journal : J. Med. Chem.
Title : Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase.
Year : 1997
Volume : 40
Issue : 20
First Page : 3228
Last Page : 3233
Authors : Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R.
Abstract : Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB1 and CB2 (Ki values of 38.0 +/- 7.2 and 26.6 +/- 5.5 nM, respectively) and to inhibit CB1-mediated adenylylcyclase with an EC50 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).
|
Binding to Cannabinoid receptor 1 using African green monkey (COS-7) cells transfected with the cDNA of rat CB1.
|
None
|
80.3
nM
|
|
Journal : J. Med. Chem.
Title : Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase.
Year : 1997
Volume : 40
Issue : 20
First Page : 3228
Last Page : 3233
Authors : Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R.
Abstract : Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB1 and CB2 (Ki values of 38.0 +/- 7.2 and 26.6 +/- 5.5 nM, respectively) and to inhibit CB1-mediated adenylylcyclase with an EC50 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).
|
Compound was evaluated for its ability to displace specifically bound [3H]CP-55940 from a Cannabinoid receptor 1 enriched rat brain microsome preparation.
|
None
|
47.6
nM
|
|
Journal : J. Med. Chem.
Title : Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs.
Year : 1996
Volume : 39
Issue : 19
First Page : 3790
Last Page : 3796
Authors : Busch-Petersen J, Hill WA, Fan P, Khanolkar A, Xie XQ, Tius MA, Makriyannis A.
Abstract : The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.
|
Evaluated for its binding affinity towards Cannabinoid receptor 1 (CB1)
|
None
|
41.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol.
Year : 1998
Volume : 41
Issue : 22
First Page : 4400
Last Page : 4407
Authors : Singer M, Ryan WJ, Saha B, Martin BR, Razdan RK.
Abstract : The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1', 1'-dimethyl-Delta8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a-h. The pharmacological profile indicated that the cyano analogues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency was also retained in analogue 2c. In contrast the sulfonamide analogue 2d was unique as it had greater affinity than Delta9-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyano or an amide substituent in the side chain of Delta8-THC-DMH can enhance potency and can also lead to compounds with a unique profile which have high binding affinity and are practically devoid of agonist effects.
|
Compound was evaluated for Pharmacological response in the Cannabinoid receptor 1
|
None
|
41.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor.
Year : 1996
Volume : 39
Issue : 20
First Page : 3875
Last Page : 3877
Authors : Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH.
|
Inhibitory activity of 1 uM against human Cannabinoid receptor 2-mediated adenylyl cyclase using African green monkey (COS-7) cells transfected with the cDNA of human CB2 receptor
|
None
|
21.0
%
|
|
Journal : J. Med. Chem.
Title : Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase.
Year : 1997
Volume : 40
Issue : 20
First Page : 3228
Last Page : 3233
Authors : Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R.
Abstract : Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB1 and CB2 (Ki values of 38.0 +/- 7.2 and 26.6 +/- 5.5 nM, respectively) and to inhibit CB1-mediated adenylylcyclase with an EC50 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).
|
Ability to bind with Cannabinoid receptor 2 using [H]CP-55940 as radioligand from cloned human receptor preparation
|
None
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor.
Year : 1996
Volume : 39
Issue : 20
First Page : 3875
Last Page : 3877
Authors : Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH.
|
Binding affinity to Cannabinoid receptor 2 using African green monkey (COS-7) cells Chinese hamster ovary(CHO) cells transfected with the cDNA of human CB2
|
None
|
32.2
nM
|
|
Journal : J. Med. Chem.
Title : Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase.
Year : 1997
Volume : 40
Issue : 20
First Page : 3228
Last Page : 3233
Authors : Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R.
Abstract : Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB1 and CB2 (Ki values of 38.0 +/- 7.2 and 26.6 +/- 5.5 nM, respectively) and to inhibit CB1-mediated adenylylcyclase with an EC50 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).
|
Binding affinity towards Cannabinoid receptor 2 using CP-55940 as radioligand in HEK293 EBNA cells
|
None
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids.
Year : 2003
Volume : 13
Issue : 20
First Page : 3487
Last Page : 3490
Authors : Krishnamurthy M, Ferreira AM, Moore BM.
Abstract : A series of novel phenyl substituted side-chain analogues of classical cannabinoids were synthesized and their CB1 and CB2 binding affinities were evaluated relative to Delta(8)-THC and compound 2. CB1 and CB2 binding assays indicate that the dimethyl and ketone analogues (3) and (6) display selectivity for the CB2 receptor in comparison to delta(8)-THC and compound 2. This study provides newer insights into the geometrical and functional group requirements of the ligand binding pockets of the CB1 and the CB2 receptors.
|
Binding affinity was determined for Cannabinoid receptor 2
|
None
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel cannabinol probes for CB1 and CB2 cannabinoid receptors.
Year : 2000
Volume : 43
Issue : 20
First Page : 3778
Last Page : 3785
Authors : Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK.
Abstract : The observation that the phenolic hydroxyl of THCs was important for binding to the CB1 receptor but not as critical for binding to the CB2 receptor prompted us to extend this finding to the cannabinol (CBN) series. To study the SAR of CBN analogues, CBN derivatives with substitution at the C-1, C-3, and C-9 positions were chosen since these positions have played a key role in the SAR of THCs. CBN-3-(1',1'-dimethylheptyl) analogues were prepared by sulfur dehydrogenation of Delta(8)-THC-3-(1',1'-dimethylheptyl) analogues. 9-Substituted CBN analogues were prepared by the standard sulfur dehydrogenation of 9-substituted Delta(8)-THC analogues (Scheme 1), which in turn were prepared following our previous procedure using selenium dioxide oxidation of the corresponding Delta(8)-THCs followed by sodium chlorite oxidation to give the 9-carboxy-Delta(8)-THC derivatives. 11-Hydroxy-CBN analogues were prepared from the corresponding 9-carbomethoxy-CBN analogues by reduction with LiAlH(4). Deoxy-CBN analogue 14 was prepared from the corresponding Delta(8)-THC analogue 11 by conversion of the phenolic hydroxyl to the phosphate derivative 12, followed by lithium ammonia reduction to provide the deoxy-Delta(8)-THC analogue 13, which in turn was dehydrogenated with sulfur to provide the deoxy-CBN analogue 14 (Scheme 2). The various analogues were assayed for binding both to the brain and the peripheral cannabinoid receptors (CB1 and CB2). We have found that the binding profile differs widely between the CBN and the THC series. Specifically, in the CBN series the removal of the phenolic hydroxyl decreases binding affinity to both the CB1 and CB2 receptors, whereas in the THC series, CB1 affinity is selectively reduced. Thus, in the CBN series, the selectivity of binding observed with the removal of the hydroxy group is decreased severalfold as compared to what occurs in the THC series. Generally, high affinity for the CB2 receptor was found in analogues when the phenolic hydroxyl was present. The 3-(1', 1'-dimethylheptyl) derivatives were found to have much higher affinities than the CBN analogues, which is in complete agreement with previously reported work by Rhee et al.
|
Compound was evaluated for its ability to displace specifically bound [3H]CP-55940 from a Cannabinoid receptor 2 enriched mouse spleen preparation.
|
None
|
39.3
nM
|
|
Journal : J. Med. Chem.
Title : Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs.
Year : 1996
Volume : 39
Issue : 19
First Page : 3790
Last Page : 3796
Authors : Busch-Petersen J, Hill WA, Fan P, Khanolkar A, Xie XQ, Tius MA, Makriyannis A.
Abstract : The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.
|
In vitro inhibition of electrically induced contractions in isolated mouse vas deferens (MVD) preparations.
|
Mus musculus
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : C-Attached aminoalkylindoles: potent cannabinoid mimetics
Year : 1996
Volume : 6
Issue : 1
First Page : 17
Last Page : 22
Authors : D'Ambra TE, Eissenstat MA, Abt J, Ackerman JH, Bacon ER, Bell MR, Carabateas PM, Josef KA, Kumar V, Weaver JD, Arnold R, Casiano FM, Chippari SM, Haycock DA, Kuster JE, Luttinger DA, Stevenson JI, Ward SJ, Hill W, Khanolkar A, Makriyannis A
|
Concentration required to inhibit electrically induced contractions in isolated mouse vas deferens preparation in vitro
|
Mus musculus
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics.
Year : 1995
Volume : 38
Issue : 16
First Page : 3094
Last Page : 3105
Authors : Eissenstat MA, Bell MR, D'Ambra TE, Alexander EJ, Daum SJ, Ackerman JH, Gruett MD, Kumar V, Estep KG, Olefirowicz EM.
Abstract : Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands. In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of [3H]Win 55212-2 (5). Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists. The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position. A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist. Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids. The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors make sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid. Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).
|
Binding affinity for cannabinoid receptor 1
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications.
Year : 2005
Volume : 48
Issue : 16
First Page : 5059
Last Page : 5087
Authors : Lambert DM, Fowler CJ.
|
Binding affinity for cannabinoid receptor 2
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications.
Year : 2005
Volume : 48
Issue : 16
First Page : 5059
Last Page : 5087
Authors : Lambert DM, Fowler CJ.
|
Binding affinity to displace [3H]CP-55940 from CB1 receptor of rat brain
|
Rattus norvegicus
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles.
Year : 2005
Volume : 15
Issue : 18
First Page : 4110
Last Page : 4113
Authors : Huffman JW, Szklennik PV, Almond A, Bushell K, Selley DE, He H, Cassidy MP, Wiley JL, Martin BR.
Abstract : A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPgammaS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.
|
Binding affinity to displace [3H]CP-55940 from cloned human CB2 receptor
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles.
Year : 2005
Volume : 15
Issue : 18
First Page : 4110
Last Page : 4113
Authors : Huffman JW, Szklennik PV, Almond A, Bushell K, Selley DE, He H, Cassidy MP, Wiley JL, Martin BR.
Abstract : A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPgammaS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.
|
Inhibitory potency against fatty acid amide hydrolase activity in mouse brain microsomes in presence of 58 uM anandamide at 160 uM
|
Mus musculus
|
31.0
%
|
|
Journal : J. Med. Chem.
Title : The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications.
Year : 2005
Volume : 48
Issue : 16
First Page : 5059
Last Page : 5087
Authors : Lambert DM, Fowler CJ.
|
Displacement of [35S]GTP-gamma-S from rat cerebellar CB1 receptor
|
Rattus norvegicus
|
199.53
nM
|
|
Journal : J. Med. Chem.
Title : 3D-QSAR studies on cannabinoid CB1 receptor agonists: G-protein activation as biological data.
Year : 2006
Volume : 49
Issue : 2
First Page : 554
Last Page : 566
Authors : Salo OM, Savinainen JR, Parkkari T, Nevalainen T, Lahtela-Kakkonen M, Gynther J, Laitinen JT, Järvinen T, Poso A.
Abstract : G-protein activation via the CB1 receptor was determined for a group of various CB1 ligands and utilized as biological activity data in subsequent CoMFA and CoMSIA studies. Both manual techniques and automated docking at CB1 receptor models were used to obtain a common alignment of endocannabinoid and classical cannabinoid derivatives. In the final alignment models, the endocannabinoid headgroup occupies a unique region distinct from the classical cannabinoid structures, supporting the hypothesis that these structurally diverse molecules overlap only partially within the receptor binding site. Both CoMFA and CoMSIA produce statistically significant models based on the manual alignment and a docking alignment at one receptor conformer. Leave-half-out cross-validation and progressive scrambling were successfully used in assessing the predictivity of the QSAR models.
|
Binding affinity to human CB2 receptor
|
Homo sapiens
|
3.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: orally bioavailable compounds.
Year : 2007
Volume : 17
Issue : 14
First Page : 3925
Last Page : 3929
Authors : Kai H, Morioka Y, Tomida M, Takahashi T, Hattori M, Hanasaki K, Koike K, Chiba H, Shinohara S, Kanemasa T, Iwamoto Y, Takahashi K, Yamaguchi Y, Baba T, Yoshikawa T, Takenaka H.
Abstract : Structure-activity relationships and efforts to optimize the pharmacokinetic profile of a class of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among the compounds examined, compound 14 showed potent affinity and high selectivity for CB2, and compound 23 showed potent affinities against CB1 and CB2. These compounds displayed oral bioavailability.
|
Binding affinity to human CB1 receptor
|
Homo sapiens
|
17.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: orally bioavailable compounds.
Year : 2007
Volume : 17
Issue : 14
First Page : 3925
Last Page : 3929
Authors : Kai H, Morioka Y, Tomida M, Takahashi T, Hattori M, Hanasaki K, Koike K, Chiba H, Shinohara S, Kanemasa T, Iwamoto Y, Takahashi K, Yamaguchi Y, Baba T, Yoshikawa T, Takenaka H.
Abstract : Structure-activity relationships and efforts to optimize the pharmacokinetic profile of a class of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among the compounds examined, compound 14 showed potent affinity and high selectivity for CB2, and compound 23 showed potent affinities against CB1 and CB2. These compounds displayed oral bioavailability.
|
Binding affinity to mouse CB2 receptor
|
Mus musculus
|
9.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: orally bioavailable compounds.
Year : 2007
Volume : 17
Issue : 14
First Page : 3925
Last Page : 3929
Authors : Kai H, Morioka Y, Tomida M, Takahashi T, Hattori M, Hanasaki K, Koike K, Chiba H, Shinohara S, Kanemasa T, Iwamoto Y, Takahashi K, Yamaguchi Y, Baba T, Yoshikawa T, Takenaka H.
Abstract : Structure-activity relationships and efforts to optimize the pharmacokinetic profile of a class of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among the compounds examined, compound 14 showed potent affinity and high selectivity for CB2, and compound 23 showed potent affinities against CB1 and CB2. These compounds displayed oral bioavailability.
|
Binding affinity to mouse CB1 receptor
|
Mus musculus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: orally bioavailable compounds.
Year : 2007
Volume : 17
Issue : 14
First Page : 3925
Last Page : 3929
Authors : Kai H, Morioka Y, Tomida M, Takahashi T, Hattori M, Hanasaki K, Koike K, Chiba H, Shinohara S, Kanemasa T, Iwamoto Y, Takahashi K, Yamaguchi Y, Baba T, Yoshikawa T, Takenaka H.
Abstract : Structure-activity relationships and efforts to optimize the pharmacokinetic profile of a class of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among the compounds examined, compound 14 showed potent affinity and high selectivity for CB2, and compound 23 showed potent affinities against CB1 and CB2. These compounds displayed oral bioavailability.
|
Displacement of [3H]CP-55940 from CB1 receptor in Sprague-Dawley rat brain membrane
|
Rattus norvegicus
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940.
Year : 2008
Volume : 16
Issue : 1
First Page : 322
Last Page : 335
Authors : Huffman JW, Thompson AL, Wiley JL, Martin BR.
Abstract : A series of 1-deoxy analogs of CP-47,497 (8 and 13, n=0-7) and 1-deoxy analogs of CP-55,940 (9, n=0-7) have been synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors have been determined. Although the majority of these compounds exhibit selectivity for the CB(2) receptor, none have greater than modest affinity for either receptor. The interactions of these 1-deoxy nontraditional cannabinoids with the CB(2) receptor are discussed.
|
Displacement of [3H]CP-55940 from human cloned CB2 receptor
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940.
Year : 2008
Volume : 16
Issue : 1
First Page : 322
Last Page : 335
Authors : Huffman JW, Thompson AL, Wiley JL, Martin BR.
Abstract : A series of 1-deoxy analogs of CP-47,497 (8 and 13, n=0-7) and 1-deoxy analogs of CP-55,940 (9, n=0-7) have been synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors have been determined. Although the majority of these compounds exhibit selectivity for the CB(2) receptor, none have greater than modest affinity for either receptor. The interactions of these 1-deoxy nontraditional cannabinoids with the CB(2) receptor are discussed.
|
Displacement of [3H]CP-55940 from human CB2 receptor
|
Homo sapiens
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel benzimidazole derivatives as selective CB2 agonists.
Year : 2008
Volume : 18
Issue : 13
First Page : 3695
Last Page : 3700
Authors : Pagé D, Balaux E, Boisvert L, Liu Z, Milburn C, Tremblay M, Wei Z, Woo S, Luo X, Cheng YX, Yang H, Srivastava S, Zhou F, Brown W, Tomaszewski M, Walpole C, Hodzic L, St-Onge S, Godbout C, Salois D, Payza K.
Abstract : The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.
|
Displacement of [3H]CP-55940 from human CB1 receptor
|
Homo sapiens
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel benzimidazole derivatives as selective CB2 agonists.
Year : 2008
Volume : 18
Issue : 13
First Page : 3695
Last Page : 3700
Authors : Pagé D, Balaux E, Boisvert L, Liu Z, Milburn C, Tremblay M, Wei Z, Woo S, Luo X, Cheng YX, Yang H, Srivastava S, Zhou F, Brown W, Tomaszewski M, Walpole C, Hodzic L, St-Onge S, Godbout C, Salois D, Payza K.
Abstract : The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.
|
Agonist activity at cloned human CB2 receptor in Sf9 cells assessed as stimulation of [35S]GTPgammaS binding assay
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel benzimidazole derivatives as selective CB2 agonists.
Year : 2008
Volume : 18
Issue : 13
First Page : 3695
Last Page : 3700
Authors : Pagé D, Balaux E, Boisvert L, Liu Z, Milburn C, Tremblay M, Wei Z, Woo S, Luo X, Cheng YX, Yang H, Srivastava S, Zhou F, Brown W, Tomaszewski M, Walpole C, Hodzic L, St-Onge S, Godbout C, Salois D, Payza K.
Abstract : The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.
|
Displacement of [3H]CP-55940 from CB1 receptor
|
None
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship of substitutions at the C-1 position of Delta9-tetrahydrocannabinol.
Year : 2010
Volume : 20
Issue : 4
First Page : 1424
Last Page : 1426
Authors : Burdick D, DeOrazio R, Guzzo P, Habershaw A, Helle M, Paul B, Wolf M.
Abstract : A novel series of Delta9-tetrahydrocannabinol (Delta9-THC) analogues were synthesized to determine their potential as cannabinoid receptor modulators. Chemistry focused on conversion of the phenol of Delta9-THC to other functionality through palladium catalyzed reactions with an intermediate triflate 2. Two analogues with sub 100 nM affinity for the CB1 and CB2 receptors were identified.
|
Displacement of [3H]CP-55940 from CB2 receptor
|
None
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationship of substitutions at the C-1 position of Delta9-tetrahydrocannabinol.
Year : 2010
Volume : 20
Issue : 4
First Page : 1424
Last Page : 1426
Authors : Burdick D, DeOrazio R, Guzzo P, Habershaw A, Helle M, Paul B, Wolf M.
Abstract : A novel series of Delta9-tetrahydrocannabinol (Delta9-THC) analogues were synthesized to determine their potential as cannabinoid receptor modulators. Chemistry focused on conversion of the phenol of Delta9-THC to other functionality through palladium catalyzed reactions with an intermediate triflate 2. Two analogues with sub 100 nM affinity for the CB1 and CB2 receptors were identified.
|
Agonist activity at rat TRPA1 channel expressed in HEK293 cells assessed as increase in intracellular calcium influx
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents.
Year : 2010
Volume : 53
Issue : 14
First Page : 5085
Last Page : 5107
Authors : Baraldi PG, Preti D, Materazzi S, Geppetti P.
|
Displacement of [3H]CP-55940 from CB1 receptor in Sprague-Dawley rat brain cortex membranes
|
Rattus norvegicus
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacology of 1-methoxy analogs of CP-47,497.
Year : 2010
Volume : 18
Issue : 15
First Page : 5475
Last Page : 5482
Authors : Huffman JW, Hepburn SA, Reggio PH, Hurst DP, Wiley JL, Martin BR.
Abstract : Three 1-methoxy analogs of CP-47,497 (7, 8, and 19) have been synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors have been determined. Although these compounds exhibit selectivity for the CB(2) receptor none have significant affinity for either receptor. Modeling and receptor docking studies were carried out, which provide a rationalization for the weak affinities of these compounds for either receptor.
|
Displacement of [3H]CP-55940 from human CB2 receptor expressed in CHO cells after 1 hr by liquid scintillation spectrometry analysis
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacology of 1-methoxy analogs of CP-47,497.
Year : 2010
Volume : 18
Issue : 15
First Page : 5475
Last Page : 5482
Authors : Huffman JW, Hepburn SA, Reggio PH, Hurst DP, Wiley JL, Martin BR.
Abstract : Three 1-methoxy analogs of CP-47,497 (7, 8, and 19) have been synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors have been determined. Although these compounds exhibit selectivity for the CB(2) receptor none have significant affinity for either receptor. Modeling and receptor docking studies were carried out, which provide a rationalization for the weak affinities of these compounds for either receptor.
|
Displacement of [3H]CP-55940 from CB1 receptor in Sprague-Dawley rat brain membranes after 1 hr by liquid scintillation spectrophotometry
|
Rattus norvegicus
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-Bromo-3-(1',1'-dimethylalkyl)-1-deoxy-Δ(8)-tetrahydrocannabinols: New selective ligands for the cannabinoid CB(2) receptor.
Year : 2010
Volume : 18
Issue : 22
First Page : 7809
Last Page : 7815
Authors : Huffman JW, Hepburn SA, Lyutenko N, Thompson AL, Wiley JL, Selley DE, Martin BR.
Abstract : Δ(8)-Tetrahydrocannabinol (26), 3-(1',1'-dimethylbutyl)- (12), 3-(1',1'-dimethylpentyl)- (13), 3-(1',1'-dimethylhexyl)- (14) and 3-(1',1'-dimethylheptyl)-Δ(8)-tetrahydrocannabinol (15) have been converted into the corresponding 1-bromo-1-deoxy-Δ(8)-tetrahydrocannabinols (25, 8-11). This was accomplished using a protocol developed in our laboratory in which the trifluoromethanesulfonate of a phenol undergoes palladium mediated coupling with pinacolborane. Reaction of this dioxaborolane with aqueous-methanolic copper(II) bromide provides the aryl bromide. The affinities of these bromo cannabinoids for the cannabinoid CB(1) and CB(2) receptors were determined. All of these compounds showed selectivity for the CB(2) receptor and one of them, 1-bromo-1-deoxy-3-(1',1'-dimethylhexyl)-Δ(8)-tetrahydrocannabinol (10), exhibits 52-fold selectivity for this receptor with good (28nM) affinity.
|
Displacement of [3H]CP-55940 from human CB2 receptor expressed in CHO cells after 1 hr by liquid scintillation spectrophotometry
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1-Bromo-3-(1',1'-dimethylalkyl)-1-deoxy-Δ(8)-tetrahydrocannabinols: New selective ligands for the cannabinoid CB(2) receptor.
Year : 2010
Volume : 18
Issue : 22
First Page : 7809
Last Page : 7815
Authors : Huffman JW, Hepburn SA, Lyutenko N, Thompson AL, Wiley JL, Selley DE, Martin BR.
Abstract : Δ(8)-Tetrahydrocannabinol (26), 3-(1',1'-dimethylbutyl)- (12), 3-(1',1'-dimethylpentyl)- (13), 3-(1',1'-dimethylhexyl)- (14) and 3-(1',1'-dimethylheptyl)-Δ(8)-tetrahydrocannabinol (15) have been converted into the corresponding 1-bromo-1-deoxy-Δ(8)-tetrahydrocannabinols (25, 8-11). This was accomplished using a protocol developed in our laboratory in which the trifluoromethanesulfonate of a phenol undergoes palladium mediated coupling with pinacolborane. Reaction of this dioxaborolane with aqueous-methanolic copper(II) bromide provides the aryl bromide. The affinities of these bromo cannabinoids for the cannabinoid CB(1) and CB(2) receptors were determined. All of these compounds showed selectivity for the CB(2) receptor and one of them, 1-bromo-1-deoxy-3-(1',1'-dimethylhexyl)-Δ(8)-tetrahydrocannabinol (10), exhibits 52-fold selectivity for this receptor with good (28nM) affinity.
|
Displacement of [3H]CP55940 from human recombinant CB1 receptor expressed in HEK293 cells after 90 mins
|
Homo sapiens
|
2.8
nM
|
|
Journal : J. Nat. Prod.
Title : Cannabinomimetic lipid from a marine cyanobacterium.
Year : 2011
Volume : 74
Issue : 10
First Page : 2313
Last Page : 2317
Authors : Gutiérrez M, Pereira AR, Debonsi HM, Ligresti A, Di Marzo V, Gerwick WH.
Abstract : NMR-guided fractionation of two independent collections of the marine cyanobacteria Lyngbya majuscula obtained from Papua New Guinea and Oscillatoria sp. collected in Panama led to the isolation of the new lipids serinolamide A (3) and propenediester (4). Their structures were determined by NMR and MS data analysis. Serinolamide A (3) exhibited a moderate agonist effect and selectivity for the CB1 cannabinoid receptor (Ki=1.3 μM, >5-fold) and represents the newest addition to the known cannabinomimetic natural products of marine origin.
|
Displacement of [3H]CP55940 from human recombinant CB2 receptor expressed in HEK293 cells after 90 mins
|
Homo sapiens
|
9.5
nM
|
|
Journal : J. Nat. Prod.
Title : Cannabinomimetic lipid from a marine cyanobacterium.
Year : 2011
Volume : 74
Issue : 10
First Page : 2313
Last Page : 2317
Authors : Gutiérrez M, Pereira AR, Debonsi HM, Ligresti A, Di Marzo V, Gerwick WH.
Abstract : NMR-guided fractionation of two independent collections of the marine cyanobacteria Lyngbya majuscula obtained from Papua New Guinea and Oscillatoria sp. collected in Panama led to the isolation of the new lipids serinolamide A (3) and propenediester (4). Their structures were determined by NMR and MS data analysis. Serinolamide A (3) exhibited a moderate agonist effect and selectivity for the CB1 cannabinoid receptor (Ki=1.3 μM, >5-fold) and represents the newest addition to the known cannabinomimetic natural products of marine origin.
|
Displacement of [3H]-CP55,940 from human CB1 receptor expressed in HEK293 cells
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.
Year : 2012
Volume : 22
Issue : 4
First Page : 1619
Last Page : 1624
Authors : Cheng YX, Pourashraf M, Luo X, Srivastava S, Walpole C, Salois D, St-Onge S, Payza K, Lessard E, Yu XH, Tomaszewski MJ.
Abstract : An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.
|
Agonist activity at human CB1 receptor expressed in HEK293 EBNA cells by [35S]GTPgamma binding assay
|
Homo sapiens
|
17.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.
Year : 2012
Volume : 22
Issue : 4
First Page : 1619
Last Page : 1624
Authors : Cheng YX, Pourashraf M, Luo X, Srivastava S, Walpole C, Salois D, St-Onge S, Payza K, Lessard E, Yu XH, Tomaszewski MJ.
Abstract : An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.
|
Binding affinity to human CB2 receptor
|
Homo sapiens
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.
Year : 2012
Volume : 22
Issue : 4
First Page : 1619
Last Page : 1624
Authors : Cheng YX, Pourashraf M, Luo X, Srivastava S, Walpole C, Salois D, St-Onge S, Payza K, Lessard E, Yu XH, Tomaszewski MJ.
Abstract : An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.
|
Binding affinity to human CB2 receptor by filtration assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: steric and electronic effects of 4- and 8-halogenated naphthoyl substituents.
Year : 2012
Volume : 20
Issue : 6
First Page : 2067
Last Page : 2081
Authors : Wiley JL, Smith VJ, Chen J, Martin BR, Huffman JW.
Abstract : To develop SAR at both the cannabinoid CB(1) and CB(2) receptors for 3-(1-naphthoyl)indoles bearing moderately electron withdrawing substituents at C-4 of the naphthoyl moiety, 1-propyl and 1-pentyl-3-(4-fluoro, chloro, bromo and iodo-1-naphthoyl) derivatives were prepared. To study the steric and electronic effects of substituents at the 8-position of the naphthoyl group, the 3-(4-chloro, bromo and iodo-1-naphthoyl)indoles were also synthesized. The affinities of both groups of compounds for the CB(1) and CB(2) receptors were determined and several of them were evaluated in vivo in the mouse. The effects of these substituents on receptor affinities and in vivo activity are discussed and structure-activity relationships are presented. Although many of these compounds are selective for the CB(2) receptor, only three JWH-423, 1-propyl-3-(4-iodo-1-naphthoyl)indole, JWH-422, 2-methyl-1-propyl-3-(4-iodo-1-naphthoyl)indole, the 2-methyl analog of JWH-423 and JWH-417, 1-pentyl-3-(8-iodo-1-naphthoyl)indole, possess the desirable combination of low CB(1) affinity and good CB(2) affinity.
|
Displacement of [3H]CP55940 from CB1 receptor
|
None
|
41.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: steric and electronic effects of 4- and 8-halogenated naphthoyl substituents.
Year : 2012
Volume : 20
Issue : 6
First Page : 2067
Last Page : 2081
Authors : Wiley JL, Smith VJ, Chen J, Martin BR, Huffman JW.
Abstract : To develop SAR at both the cannabinoid CB(1) and CB(2) receptors for 3-(1-naphthoyl)indoles bearing moderately electron withdrawing substituents at C-4 of the naphthoyl moiety, 1-propyl and 1-pentyl-3-(4-fluoro, chloro, bromo and iodo-1-naphthoyl) derivatives were prepared. To study the steric and electronic effects of substituents at the 8-position of the naphthoyl group, the 3-(4-chloro, bromo and iodo-1-naphthoyl)indoles were also synthesized. The affinities of both groups of compounds for the CB(1) and CB(2) receptors were determined and several of them were evaluated in vivo in the mouse. The effects of these substituents on receptor affinities and in vivo activity are discussed and structure-activity relationships are presented. Although many of these compounds are selective for the CB(2) receptor, only three JWH-423, 1-propyl-3-(4-iodo-1-naphthoyl)indole, JWH-422, 2-methyl-1-propyl-3-(4-iodo-1-naphthoyl)indole, the 2-methyl analog of JWH-423 and JWH-417, 1-pentyl-3-(8-iodo-1-naphthoyl)indole, possess the desirable combination of low CB(1) affinity and good CB(2) affinity.
|
Displacement of [3H]-CP55,940 from human CB2 receptor transfected in CHOK1 cells
|
Homo sapiens
|
71.6
nM
|
|
Journal : J. Med. Chem.
Title : Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold.
Year : 2013
Volume : 56
Issue : 11
First Page : 4798
Last Page : 4810
Authors : Rempel V, Volz N, Gläser F, Nieger M, Bräse S, Müller CE.
Abstract : The orphan G-protein-coupled receptor GPR55, which is activated by 1-lysophosphatidylinositol and interacts with cannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson's disease, neuropathic pain, and cancer. We applied β-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure-activity relationship study for GPR55. Selectivity versus the related receptors CB1, CB2, and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2H-chromen-2-one (12, PSB-SB-489, IC50 = 1.77 μM, pA2 = 0.547 μM). Derivatives with long alkyl chains in position 7 were potent, possibly allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (69, PSB-SB-487, IC50 = 0.113 μM, KB = 0.561 μM) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC50 = 0.261 μM) were the most potent GPR55 antagonists of the present series.
|
Displacement of [3H]-CP55,940 from human CB1 receptor transfected in CHOK1 cells
|
Homo sapiens
|
3.88
nM
|
|
Journal : J. Med. Chem.
Title : Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold.
Year : 2013
Volume : 56
Issue : 11
First Page : 4798
Last Page : 4810
Authors : Rempel V, Volz N, Gläser F, Nieger M, Bräse S, Müller CE.
Abstract : The orphan G-protein-coupled receptor GPR55, which is activated by 1-lysophosphatidylinositol and interacts with cannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson's disease, neuropathic pain, and cancer. We applied β-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure-activity relationship study for GPR55. Selectivity versus the related receptors CB1, CB2, and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2H-chromen-2-one (12, PSB-SB-489, IC50 = 1.77 μM, pA2 = 0.547 μM). Derivatives with long alkyl chains in position 7 were potent, possibly allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (69, PSB-SB-487, IC50 = 0.113 μM, KB = 0.561 μM) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC50 = 0.261 μM) were the most potent GPR55 antagonists of the present series.
|
Agonist activity at human GPR18 expressed in HEK203 cells by MAP kinase assay
|
Homo sapiens
|
960.0
nM
|
|
Journal : MedChemComm
Title : Bicyclic imidazole-4-one derivatives: a new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55
Year : 2014
Volume : 5
Issue : 5
First Page : 632
Last Page : 649
Authors : Rempel V, Atzler K, Behrenswerth A, Karcz T, Schoeder C, Hinz S, Kaleta M, Thimm D, Kiec-Kononowicz K, Muller CE
|
Displacement of [3H]CP55,940 from human recombinant CB2 receptor expressed in HEK293 cells
|
Homo sapiens
|
71.6
nM
|
|
Journal : MedChemComm
Title : Bicyclic imidazole-4-one derivatives: a new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55
Year : 2014
Volume : 5
Issue : 5
First Page : 632
Last Page : 649
Authors : Rempel V, Atzler K, Behrenswerth A, Karcz T, Schoeder C, Hinz S, Kaleta M, Thimm D, Kiec-Kononowicz K, Muller CE
|
Displacement of [3H]CP55,940 from human recombinant CB1 receptor expressed in CHO-K1 cells
|
Homo sapiens
|
3.88
nM
|
|
Journal : MedChemComm
Title : Bicyclic imidazole-4-one derivatives: a new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55
Year : 2014
Volume : 5
Issue : 5
First Page : 632
Last Page : 649
Authors : Rempel V, Atzler K, Behrenswerth A, Karcz T, Schoeder C, Hinz S, Kaleta M, Thimm D, Kiec-Kononowicz K, Muller CE
|
Binding affinity to human CB1 receptor
|
Homo sapiens
|
40.7
nM
|
|
Journal : J. Med. Chem.
Title : Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists.
Year : 2013
Volume : 56
Issue : 21
First Page : 8224
Last Page : 8256
Authors : Han S, Thatte J, Buzard DJ, Jones RM.
Abstract : The cannabinoid receptor type 2 (CB2) is a class A GPCR that was cloned in 1993 while looking for an alternative receptor that could explain the pharmacological properties of Δ(9)-tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system. In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, peripheral nervous system, and gastrointestinal tract. Several "mixed" cannabinoid agonists are currently in clinical use primarily for controlling pain, and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects. Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this Perspective, we seek to provide a concise update of progress in the field.
|
Binding affinity to human CB2 receptor
|
Homo sapiens
|
36.4
nM
|
|
Journal : J. Med. Chem.
Title : Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists.
Year : 2013
Volume : 56
Issue : 21
First Page : 8224
Last Page : 8256
Authors : Han S, Thatte J, Buzard DJ, Jones RM.
Abstract : The cannabinoid receptor type 2 (CB2) is a class A GPCR that was cloned in 1993 while looking for an alternative receptor that could explain the pharmacological properties of Δ(9)-tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system. In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, peripheral nervous system, and gastrointestinal tract. Several "mixed" cannabinoid agonists are currently in clinical use primarily for controlling pain, and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects. Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this Perspective, we seek to provide a concise update of progress in the field.
|
Inhibition of mouse brain synaptosomal Lysophosphatidylcholine acyltransferase using substrate [32P]lysophosphatidylcholine and oleoyl-CoA
|
Mus musculus
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Molar volume relationships and the specific inhibition of a synaptosomal enzyme by psychoactive cannabinoids.
Year : 1978
Volume : 21
Issue : 12
First Page : 1208
Last Page : 1212
Authors : Greenberg JH, Mellors A, McGowan JC.
Abstract : The ability of a number of lipophilic compounds to inhibit the mouse-brain synaptosomal enzyme acyl coenzyme A:lysophosphatidylcholine acyltransferase has been measured in vitro. Psychoactive cannabinoids inhibit the enzyme at concentrations much lower than is predicted from their capacity to act as lipid-soluble anesthetics. Nonpsychoactive cannabinoids do not show specific inhibition. Molar volume relationships are used to show that, while all lipid-soluble molecules exert some inhibitory effect in proportion to their ability to dissolve in biological membranes, psychoactive cannabinoids have an inhibitory effect greatly in excess of their anesthetic potency. The isoprenoid convulsant thujone has been suggested to have psychoactivity similar to cannabinoids but does not mimic the cannabinoids in inhibiting the synaptosomal enzyme. Molar volumes and specific interactions are used in structure-activity correlations which yield information on the relative concentrations of biophase in drug-responsive systems and the specificity of membrane-active drugs.
|
Displacement of [3H]CP55940 from rat brain CB1 receptor
|
Rattus norvegicus
|
39.5
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : C-ring cannabinoid lactones: a novel cannabinergic chemotype.
Year : 2014
Volume : 5
Issue : 4
First Page : 400
Last Page : 404
Authors : Sharma R, Nikas SP, Guo JJ, Mallipeddi S, Wood JT, Makriyannis A.
Abstract : As a part of our controlled-deactivation ligand development project, we recently disclosed a series of (-)-Δ(8)-tetrahydrocannabinols (THCs) with a metabolically labile ester group at the 2'-position of the side chain. Now, we have replaced the C-ring in the classical THC structure with a hydrolyzable seven-membered lactone. One of the synthesized analogues binds with high affinity to the CB1 receptor (K i = 4.6 nM) and exhibits much lower affinities for the mCB2 and the hCB2. Also, in vitro functional characterization found the compound to be an agonist at rCB1. Consistent with our rational design, the lead cannabinergic lactone identified here is susceptible to metabolic inactivation by plasma esterases, while the respective acid metabolite is inactive at CB receptors. These results are highlighted with molecular modeling of the two regiosomeric lactones.
|
Displacement of [3H]CP55940 from mouse brain CB2 receptor expressed in HEK293 cells
|
Mus musculus
|
40.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : C-ring cannabinoid lactones: a novel cannabinergic chemotype.
Year : 2014
Volume : 5
Issue : 4
First Page : 400
Last Page : 404
Authors : Sharma R, Nikas SP, Guo JJ, Mallipeddi S, Wood JT, Makriyannis A.
Abstract : As a part of our controlled-deactivation ligand development project, we recently disclosed a series of (-)-Δ(8)-tetrahydrocannabinols (THCs) with a metabolically labile ester group at the 2'-position of the side chain. Now, we have replaced the C-ring in the classical THC structure with a hydrolyzable seven-membered lactone. One of the synthesized analogues binds with high affinity to the CB1 receptor (K i = 4.6 nM) and exhibits much lower affinities for the mCB2 and the hCB2. Also, in vitro functional characterization found the compound to be an agonist at rCB1. Consistent with our rational design, the lead cannabinergic lactone identified here is susceptible to metabolic inactivation by plasma esterases, while the respective acid metabolite is inactive at CB receptors. These results are highlighted with molecular modeling of the two regiosomeric lactones.
|
Antidiarrheal activity in Charles River rat assessed as inhibition of castor oil-induced diarrhea by measuring protected animals at 0.5 mg/kg, po administered 1 hr prior to castor oil challenge measured after 1 hr relative to vehicle-treated control
|
Rattus norvegicus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains.
Year : 1976
Volume : 19
Issue : 4
First Page : 461
Last Page : 471
Authors : Winn M, Arendsen D, Dodge P, Dren A, Dunnigan D, Hallas R, Hwang K, Kyncl J, Lee YH, Plotnikoff N, Young P, Zaugg H.
Abstract : Ten new delta6a,10a-THC analogs with arylalkyl side chains, one with a dimethylaminoalkyl side chain, and six heterocyclic delta6a,10a-THC analogs [8-substituted 5,5-dimethyl-10-hydroxy-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzo-pyrano[4,3-c]pyridines] were prepared. They showed pharmacological activity as analgesics, tranquilizers, antihypertensives, and hypnotics and as antisecretory, antiulcer, and antidiarrheal agents. The most potent compounds had either a 1-methyl-4-(4-fluorophenyl)butyl or a 1,2-dimethyl-4-(4-fluorophenyl)butyl side chain.
|
Antianxiety activity in albino BALB/cJ mouse assessed as decrease in foot shock-induced fighting behavior at 5 mg/kg, po by tranquilizer activity test
|
Mus musculus
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Cannabinoids. Synthesis and central nervous system activity of 8-substituted 10-hydroxy-5,5-dimethyl-5H-[1]benzopyrano[4,3-c]pyridine and derivatives.
Year : 1977
Volume : 20
Issue : 11
First Page : 1508
Last Page : 1511
Authors : Lee CM, Michaels RJ, Zaugg HE, Dren AT, Plotnikoff NP, Young PR.
|
Antianxiety activity in Long-Evens rat assessed as decrease in motor activity at 10 mg/kg, po by tranquilizer activity test
|
Rattus norvegicus
|
39.0
%
|
|
Journal : J. Med. Chem.
Title : Cannabinoids. Synthesis and central nervous system activity of 8-substituted 10-hydroxy-5,5-dimethyl-5H-[1]benzopyrano[4,3-c]pyridine and derivatives.
Year : 1977
Volume : 20
Issue : 11
First Page : 1508
Last Page : 1511
Authors : Lee CM, Michaels RJ, Zaugg HE, Dren AT, Plotnikoff NP, Young PR.
|
Antipsychotic activity in Long-Evens rat assessed as reduction in methamphetamine-induced hyperactivity at 5 mg/kg, po
|
Rattus norvegicus
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Cannabinoids. Synthesis and central nervous system activity of 8-substituted 10-hydroxy-5,5-dimethyl-5H-[1]benzopyrano[4,3-c]pyridine and derivatives.
Year : 1977
Volume : 20
Issue : 11
First Page : 1508
Last Page : 1511
Authors : Lee CM, Michaels RJ, Zaugg HE, Dren AT, Plotnikoff NP, Young PR.
|
Displacement of [3H]CP55940 from human cannabinoid CB1 receptor expressed in CHO-K1 cells by liquid scintillation counting
|
Homo sapiens
|
22.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors.
Year : 2014
Volume : 85
First Page : 77
Last Page : 86
Authors : Rosati O, Messina F, Pelosi A, Curini M, Petrucci V, Gertsch J, Chicca A.
Abstract : Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, Δ(9)-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.
|
Displacement of [3H]CP55940 from human cannabinoid CB2 receptor expressed in CHO-K1 cells by liquid scintillation counting
|
Homo sapiens
|
46.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors.
Year : 2014
Volume : 85
First Page : 77
Last Page : 86
Authors : Rosati O, Messina F, Pelosi A, Curini M, Petrucci V, Gertsch J, Chicca A.
Abstract : Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, Δ(9)-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.
|
Partial agonist activity at human cannabinoid CB2 receptor expressed in CHO-K1 cells assessed as [S35]GTPgammaS binding by scintillation counting
|
Homo sapiens
|
12.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors.
Year : 2014
Volume : 85
First Page : 77
Last Page : 86
Authors : Rosati O, Messina F, Pelosi A, Curini M, Petrucci V, Gertsch J, Chicca A.
Abstract : Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, Δ(9)-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.
|
Partial agonist activity at human cannabinoid CB1 receptor expressed in CHO-K1 cells assessed as [S35]GTPgammaS binding by scintillation counting
|
Homo sapiens
|
77.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors.
Year : 2014
Volume : 85
First Page : 77
Last Page : 86
Authors : Rosati O, Messina F, Pelosi A, Curini M, Petrucci V, Gertsch J, Chicca A.
Abstract : Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, Δ(9)-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands.
|
Displacement of [3H]CP-55,940 from CB1 receptor in B6SJL mouse brain membrane after 90 mins by liquid scintillation spectrophotometric analysis
|
Mus musculus
|
15.3
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands.
Year : 2012
Volume : 40
Issue : 11
First Page : 2174
Last Page : 2184
Authors : Chimalakonda KC, Seely KA, Bratton SM, Brents LK, Moran CL, Endres GW, James LP, Hollenberg PF, Prather PL, Radominska-Pandya A, Moran JH.
Abstract : Abuse of synthetic cannabinoids (SCs), such as [1-naphthalenyl-(1-pentyl-1H-indol-3-yl]-methanone (JWH-018) and [1-(5-fluoropentyl)-1H-indol-3-yl]-1-naphthalenyl-methanone (AM2201), is increasing at an alarming rate. Although very little is known about the metabolism and toxicology of these popular designer drugs, mass spectrometric analysis of human urine specimens after JWH-018 and AM2201 exposure identified monohydroxylated and carboxylated derivatives as major metabolites. The present study extends these initial findings by testing the hypothesis that JWH-018 and its fluorinated counterpart AM2201 are subject to cytochrome P450 (P450)-mediated oxidation, forming potent hydroxylated metabolites that retain significant affinity and activity at the cannabinoid 1 (CB(1)) receptor. Kinetic analysis using human liver microsomes and recombinant human protein identified CYP2C9 and CYP1A2 as major P450s involved in the oxidation of the JWH-018 and AM2201. In vitro metabolite formation mirrored human urinary metabolic profiles, and each of the primary enzymes exhibited high affinity (K(m) = 0.81-7.3 μM) and low to high reaction velocities (V(max) = 0.0053-2.7 nmol of product · min(-1) · nmol protein(-1)). The contribution of CYP2C19, 2D6, 2E1, and 3A4 in the hepatic metabolic clearance of these synthetic cannabinoids was minimal (f(m) = <0.2). In vitro studies demonstrated that the primary metabolites produced in humans display high affinity and intrinsic activity at the CB(1) receptor, which was attenuated by the CB(1) receptor antagonist (6aR,10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran (O-2050). Results from the present study provide critical, missing data related to potential toxicological properties of "K2" parent compounds and their human metabolites, including mechanism(s) of action at cannabinoid receptors.
|
Displacement of [3H]CP55940 from full length human recombinant CB1 receptor expressed in HEK293 cells after 90 mins by scintillation counting analysis
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa.
Year : 2015
Volume : 78
Issue : 6
First Page : 1271
Last Page : 1276
Authors : Radwan MM, ElSohly MA, El-Alfy AT, Ahmed SA, Slade D, Husni AS, Manly SP, Wilson L, Seale S, Cutler SJ, Ross SA.
Abstract : Seven new naturally occurring hydroxylated cannabinoids (1-7), along with the known cannabiripsol (8), have been isolated from the aerial parts of high-potency Cannabis sativa. The structures of the new compounds were determined by 1D and 2D NMR spectroscopic analysis, GC-MS, and HRESIMS as 8α-hydroxy-Δ(9)-tetrahydrocannabinol (1), 8β-hydroxy-Δ(9)-tetrahydrocannabinol (2), 10α-hydroxy-Δ(8)-tetrahydrocannabinol (3), 10β-hydroxy-Δ(8)-tetrahydrocannabinol (4), 10α-hydroxy-Δ(9,11)-hexahydrocannabinol (5), 9β,10β-epoxyhexahydrocannabinol (6), and 11-acetoxy-Δ(9)-tetrahydrocannabinolic acid A (7). The binding affinity of isolated compounds 1-8, Δ(9)-tetrahydrocannabinol, and Δ(8)-tetrahydrocannabinol toward CB1 and CB2 receptors as well as their behavioral effects in a mouse tetrad assay were studied. The results indicated that compound 3, with the highest affinity to the CB1 receptors, exerted the most potent cannabimimetic-like actions in the tetrad assay, while compound 4 showed partial cannabimimetic actions. Compound 2, on the other hand, displayed a dose-dependent hypolocomotive effect only.
|
Displacement of [3H]CP55940 from full length human recombinant CB2 receptor expressed in HEK293 cells after 90 mins by scintillation counting analysis
|
Homo sapiens
|
42.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa.
Year : 2015
Volume : 78
Issue : 6
First Page : 1271
Last Page : 1276
Authors : Radwan MM, ElSohly MA, El-Alfy AT, Ahmed SA, Slade D, Husni AS, Manly SP, Wilson L, Seale S, Cutler SJ, Ross SA.
Abstract : Seven new naturally occurring hydroxylated cannabinoids (1-7), along with the known cannabiripsol (8), have been isolated from the aerial parts of high-potency Cannabis sativa. The structures of the new compounds were determined by 1D and 2D NMR spectroscopic analysis, GC-MS, and HRESIMS as 8α-hydroxy-Δ(9)-tetrahydrocannabinol (1), 8β-hydroxy-Δ(9)-tetrahydrocannabinol (2), 10α-hydroxy-Δ(8)-tetrahydrocannabinol (3), 10β-hydroxy-Δ(8)-tetrahydrocannabinol (4), 10α-hydroxy-Δ(9,11)-hexahydrocannabinol (5), 9β,10β-epoxyhexahydrocannabinol (6), and 11-acetoxy-Δ(9)-tetrahydrocannabinolic acid A (7). The binding affinity of isolated compounds 1-8, Δ(9)-tetrahydrocannabinol, and Δ(8)-tetrahydrocannabinol toward CB1 and CB2 receptors as well as their behavioral effects in a mouse tetrad assay were studied. The results indicated that compound 3, with the highest affinity to the CB1 receptors, exerted the most potent cannabimimetic-like actions in the tetrad assay, while compound 4 showed partial cannabimimetic actions. Compound 2, on the other hand, displayed a dose-dependent hypolocomotive effect only.
|
Displacement of [3H]HU-243 from CB1 receptor in Sprague-Dawley rat brain incubated for 90 mins
|
Rattus norvegicus
|
36.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties.
Year : 2016
Volume : 112
First Page : 66
Last Page : 80
Authors : Deiana V, Gómez-Cañas M, Pazos MR, Fernández-Ruiz J, Asproni B, Cichero E, Fossa P, Muñoz E, Deligia F, Murineddu G, García-Arencibia M, Pinna GA.
Abstract : Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2 receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB1 and CB2 receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4-dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed the highest CB2 receptor affinity (Ki = 4 nM) and remarkable selectivity (KiCB1/KiCB2 = 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki = 6 nM), for the bornyl analogue (compound 14: Ki = 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki = 69 nM). Compounds 10 and 14 were also highly selective for the CB2 receptor (KiCB1/KiCB2 > 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2 = 27). The four compounds were also subjected to GTPγS binding analysis showing antagonist/inverse agonist properties (IC50 for compound 14 = 27 nM, for 15 = 51 nM, for 10 = 80 nM and for 6 = 294 nM), and this activity was confirmed for the three more active compounds in a CB2 receptor-specific in vitro bioassay consisting in the quantification of prostaglandin E2 release by LPS-stimulated BV2 cells, in the presence and absence of WIN55,212-2 and/or the investigated compounds. Modelling studies were also conducted with the four compounds, which conformed with the structural requirements stated for the binding of antagonist compounds to the human CB2 receptor.
|
Agonist activity at CB1 receptor (unknown origin)
|
Homo sapiens
|
39.5
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor.
Year : 2016
Volume : 124
First Page : 17
Last Page : 35
Authors : Romero-Parra J, Mella-Raipán J, Palmieri V, Allarà M, Torres MJ, Pessoa-Mahana H, Iturriaga-Vásquez P, Escobar R, Faúndez M, Di Marzo V, Pessoa-Mahana CD.
Abstract : Herein we report the design, synthesis, bioinformatic and biological studies of benzimidazole and benzothiophene derivatives as new cannabinoid receptor ligands. To test the hypothesis that the lack of a hydrogen bond interaction between benzimidazole and benzothiophene derivatives with Lys192 reduces their affinity for CB1 receptors (as we previously reported) and leads to CB2 selectivity, most of the tested compounds do not exhibit hydrogen bond acceptors. All compounds displayed mostly CB2 selectivity, although this was more pronounced in the benzimidazoles derivatives. Furthermore, docking assays revealed a ∏-cation interaction with Lys109 which could play a key role for the CB2 selectivity index. The series displayed low toxicity on five different cell lines. Derivative 8f presented the best binding profile (Ki = 0.08 μM), high selectivity index (KiCB1/KiCB2) and a low citoxicity. Interestingly, in cell viability experiments, using HL-60 cells (expressing exclusively CB2 receptors), all synthesised compounds were shown to be cytotoxic, suggesting that a CB2 agonist response may be involved.
|
Agonist activity at CB2 receptor (unknown origin)
|
Homo sapiens
|
40.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor.
Year : 2016
Volume : 124
First Page : 17
Last Page : 35
Authors : Romero-Parra J, Mella-Raipán J, Palmieri V, Allarà M, Torres MJ, Pessoa-Mahana H, Iturriaga-Vásquez P, Escobar R, Faúndez M, Di Marzo V, Pessoa-Mahana CD.
Abstract : Herein we report the design, synthesis, bioinformatic and biological studies of benzimidazole and benzothiophene derivatives as new cannabinoid receptor ligands. To test the hypothesis that the lack of a hydrogen bond interaction between benzimidazole and benzothiophene derivatives with Lys192 reduces their affinity for CB1 receptors (as we previously reported) and leads to CB2 selectivity, most of the tested compounds do not exhibit hydrogen bond acceptors. All compounds displayed mostly CB2 selectivity, although this was more pronounced in the benzimidazoles derivatives. Furthermore, docking assays revealed a ∏-cation interaction with Lys109 which could play a key role for the CB2 selectivity index. The series displayed low toxicity on five different cell lines. Derivative 8f presented the best binding profile (Ki = 0.08 μM), high selectivity index (KiCB1/KiCB2) and a low citoxicity. Interestingly, in cell viability experiments, using HL-60 cells (expressing exclusively CB2 receptors), all synthesised compounds were shown to be cytotoxic, suggesting that a CB2 agonist response may be involved.
|
[35S]GTPγS Binding Assay: [35S]GTPγS binding was performed as previously described [Brents et al., PLoS One, 6:e21917]. Briefly, 25 μg of mouse brain homogenates were incubated for 30 minutes at 30° C. with 0.1 nM [35S]GTPγS, 10 μM GDP, and either cannabinoid+/−antagonist, 10 μM unlabeled GTPγS (non-specific binding) or vehicle (total binding), in triplicate, in a volume of 1 mL of buffer containing 20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, 20 units/L adenosine deaminase, 0.05% BSA and the appropriate DMSO (0.1%) and/or ethanol (<0.2%) vehicle. Assay buffer containing 100 mM KCl, instead of 100 mM NaCl, was used to increase basal G-protein activity in experiments examining inverse agonism. Reactions were terminated by quick vacuum filtration through Whatman GF/B glass fiber filters, followed by five washes with ice-cold buffer (20 mM HEPES, 0.05% BSA). Filters were immediately placed into 7 mL scintillation vials to which 4 mL of ScintiVerse™ BD Cocktail scintillation fluid was added. Bound radioactivity was determined after overnight incubation at room temperature and shaking by liquid scintillation spectrophotometry with an efficiency of 93% (Tri Carb 2100 TR Liquid Scintillation Analyzer, Packard Instrument Company, Meriden, Conn.).
|
None
|
77.0
nM
|
|
Title : Use of the aminoalkylindole JWH-073-M4 and related compounds as neutral CB1 receptor antagonists for the treatment of alcoholism, drug abuse, obesity, and obesity-related diseases
Year : 2016
|
Agonist activity at recombinant human CB1 receptor expressed in CHO-K1 cells assessed as increase in cAMP accumulation after 20 mins by HTRF assay
|
Homo sapiens
|
10.2
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, Structure-Activity Relationship Studies, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase.
Year : 2017
Volume : 60
Issue : 6
First Page : 2287
Last Page : 2304
Authors : De Simone A, Russo D, Ruda GF, Micoli A, Ferraro M, Di Martino RM, Ottonello G, Summa M, Armirotti A, Bandiera T, Cavalli A, Bottegoni G.
Abstract : We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB1. To understand the unexpected affinity for the CB1 receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.
|
Binding affinity to human CB1 receptor
|
Homo sapiens
|
40.0
nM
|
|
Journal : J Nat Prod
Title : Isolation of a High-Affinity Cannabinoid for the Human CB1 Receptor from a Medicinal Cannabis sativa Variety: Δ9-Tetrahydrocannabutol, the Butyl Homologue of Δ9-Tetrahydrocannabinol.
Year : 2020
Volume : 83
Issue : 1
First Page : 88
Last Page : 98
Authors : Linciano P, Citti C, Luongo L, Belardo C, Maione S, Vandelli MA, Forni F, Gigli G, Laganà A, Montone CM, Cannazza G.
Abstract : The butyl homologues of Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabutol (Δ9-THCB), and cannabidiol, cannabidibutol (CBDB), were isolated from a medicinal Cannabis sativa variety (FM2) inflorescence. Appropriate spectroscopic and spectrometric characterization, including NMR, UV, IR, ECD, and HRMS, was carried out on both cannabinoids. The chemical structures and absolute configurations of the isolated cannabinoids were confirmed by comparison with the spectroscopic data of the respective compounds obtained by stereoselective synthesis. The butyl homologue of Δ9-THC, Δ9-THCB, showed an affinity for the human CB1 (Ki = 15 nM) and CB2 receptors (Ki = 51 nM) comparable to that of (-)-trans-Δ9-THC. Docking studies suggested the key bonds responsible for THC-like binding affinity for the CB1 receptor. The formalin test in vivo was performed on Δ9-THCB in order to reveal possible analgesic and anti-inflammatory properties. The tetrad test in mice showed a partial agonistic activity of Δ9-THCB toward the CB1 receptor.
|
Displacement of [3H]JWH-018 from CB1R/CB2R in Wistar rat brain membranes after 60 mins by liquid scintillation analysis
|
Rattus norvegicus
|
82.0
nM
|
|
Journal : Eur J Med Chem
Title : Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors.
Year : 2019
Volume : 178
First Page : 571
Last Page : 588
Authors : Dvorácskó S, Keresztes A, Mollica A, Stefanucci A, Macedonio G, Pieretti S, Zádor F, Walter FR, Deli MA, Kékesi G, Bánki L, Tuboly G, Horváth G, Tömböly C.
Abstract : In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB<sub>1</sub> and CB<sub>2</sub> cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [<sup>35</sup>S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB<sub>2</sub>, whereas 19 mainly CB<sub>1</sub>) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 μg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.
|
Inverse agonist activity at mouse CB2 receptor expressed in HEK293 cells assessed as inhibition of forskolin-mediated cAMP accumulation after 5 mins by fluorescence assay
|
Mus musculus
|
7.3
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.
|
Inhibition of LPS-induced PGE2 production in mouse J774 cells at 10 uM incubated for 24 hrs by enzyme immunoassay relative to control
|
Mus musculus
|
60.0
%
|
|
Journal : Bioorg Med Chem
Title : Eicosanoid mediation of cannabinoid actions.
Year : 2019
Volume : 27
Issue : 13
First Page : 2718
Last Page : 2728
Authors : Burstein SH.
Abstract : Interactions between cannabinoids and eicosanoids have been observed for the last several decades and account for a variety of cannabinoid actions. These were seen both in vitro and in vivo and may provide a molecular basis for these actions. Some of the topics included in this review are; effects on adenylate cyclase activity, alteration of behavioral responses, reduction of pain sensation, reduction and resolution of inflammation, hypotensive and vasorelaxant responses, anti-cancer and anti-metastatic activities, reduction of intraocular pressure and others. The most widely studied cannabinoids so far are tetrahydrocannabinol and cannabidiol. However, synthetic agents such as CP55,940, ajulemic acid, JWH-133 and WIN-55,212-2 were also investigated for interaction with eicosanoids. The endocannabinoids anandamide and 2-arachidonoylglycerol have been examined as well. Among the eicosanoids mediating cannabinoid actions are PGE<sub>2</sub>, 15-deoxy-Δ<sup>12,14</sup>-prostaglandin-J<sub>2</sub>, lipoxin A<sub>4</sub>, lipoxin B<sub>4</sub>, and leukotriene B<sub>4</sub>. Enzyme activities involved include monoacylglycerylipase, adenylatecyclase, phospholipase A<sub>2</sub>, cyclooxygenases-1, 2 and 5, lipoxygenases-12 and 15. Receptors involved include CB1, CB2 and the EP3 and EP3 prostanoid receptors. While not all cannabinoid activities can be accounted for, many are best explained by eicosanoid participation. The recent surge in interest in "medical marijuana" makes understanding mechanisms of cannabinoid actions particularly important.
|
Binding affinity to CB1 receptor (unknown origin)
|
Homo sapiens
|
41.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis, molecular modeling and SAR study of novel pyrazolo[5,1-f][1,6]naphthyridines as CB<sub>2</sub> receptor antagonists/inverse agonists.
Year : 2016
Volume : 24
Issue : 21
First Page : 5291
Last Page : 5301
Authors : Dore A, Asproni B, Scampuddu A, Gessi S, Murineddu G, Cichero E, Fossa P, Merighi S, Bencivenni S, Pinna GA.
Abstract : Pyrazolo[5,1-f][1,6]naphthyridine-carboxamide derivatives were synthesized and evaluated for the affinity at CB<sub>1</sub> and CB<sub>2</sub> receptors. Based on the AgOTf and proline-cocatalyzed multicomponent methodology, the ethyl 5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (12) and ethyl 5-(2,4-dichlorophenyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (13) intermediates were synthesized from the appropriate o-alkynylaldehydes, p-toluenesulfonyl hydrazide and ethyl pyruvate. Most of the novel compounds feature a p-tolyl (8a-i) or a 2,4-dichlorophenyl (8j) motif at the C<sub>5</sub>-position of the tricyclic pyrazolo[5,1-f][1,6]naphthyridine scaffold. Structural variation on the carboxamide moiety at the C<sub>2</sub>-position includes basic monocyclic, terpenoid and adamantine-based amines. Among these derivatives, compound 8h (N-adamant-1-yl-5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxamide) exhibited the highest CB<sub>2</sub> receptor affinity (K<sub>i</sub>=33nM) and a high degree of selectivity (K<sub>i</sub>CB<sub>1</sub>/K<sub>i</sub>CB<sub>2</sub>=173:1), whereas a similar trend in the near nM range was seen for the bornyl analogue (compound 8f, K<sub>i</sub>=53nM) and the myrtanyl derivative 8j (K<sub>i</sub>=67nM). Effects of 8h, 8f and 8j on forskolin-stimulated cAMP levels were determined, showing antagonist/inverse agonist properties for such compounds. Docking studies conducted for these derivatives and the reference antagonist/inverse agonist compound 4 (SR144528) disclosed the specific pattern of interactions probably related to the pyrazolo[5,1-f][1,6]naphthyridine scaffold as CB<sub>2</sub> inverse agonists.
|
Binding affinity to CB2 receptor (unknown origin)
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis, molecular modeling and SAR study of novel pyrazolo[5,1-f][1,6]naphthyridines as CB<sub>2</sub> receptor antagonists/inverse agonists.
Year : 2016
Volume : 24
Issue : 21
First Page : 5291
Last Page : 5301
Authors : Dore A, Asproni B, Scampuddu A, Gessi S, Murineddu G, Cichero E, Fossa P, Merighi S, Bencivenni S, Pinna GA.
Abstract : Pyrazolo[5,1-f][1,6]naphthyridine-carboxamide derivatives were synthesized and evaluated for the affinity at CB<sub>1</sub> and CB<sub>2</sub> receptors. Based on the AgOTf and proline-cocatalyzed multicomponent methodology, the ethyl 5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (12) and ethyl 5-(2,4-dichlorophenyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (13) intermediates were synthesized from the appropriate o-alkynylaldehydes, p-toluenesulfonyl hydrazide and ethyl pyruvate. Most of the novel compounds feature a p-tolyl (8a-i) or a 2,4-dichlorophenyl (8j) motif at the C<sub>5</sub>-position of the tricyclic pyrazolo[5,1-f][1,6]naphthyridine scaffold. Structural variation on the carboxamide moiety at the C<sub>2</sub>-position includes basic monocyclic, terpenoid and adamantine-based amines. Among these derivatives, compound 8h (N-adamant-1-yl-5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxamide) exhibited the highest CB<sub>2</sub> receptor affinity (K<sub>i</sub>=33nM) and a high degree of selectivity (K<sub>i</sub>CB<sub>1</sub>/K<sub>i</sub>CB<sub>2</sub>=173:1), whereas a similar trend in the near nM range was seen for the bornyl analogue (compound 8f, K<sub>i</sub>=53nM) and the myrtanyl derivative 8j (K<sub>i</sub>=67nM). Effects of 8h, 8f and 8j on forskolin-stimulated cAMP levels were determined, showing antagonist/inverse agonist properties for such compounds. Docking studies conducted for these derivatives and the reference antagonist/inverse agonist compound 4 (SR144528) disclosed the specific pattern of interactions probably related to the pyrazolo[5,1-f][1,6]naphthyridine scaffold as CB<sub>2</sub> inverse agonists.
|
Displacement of [3H]CP-55,940 from human CB1 receptor expressed in CHO cells incubated for 1 hr by liquid scintillation spectrometry
|
Homo sapiens
|
40.7
nM
|
|
Journal : J Med Chem
Title : The Essential Medicinal Chemistry of Cannabidiol (CBD).
Year : 2020
Volume : 63
Issue : 21
First Page : 12137
Last Page : 12155
Authors : Nelson KM,Bisson J,Singh G,Graham JG,Chen SN,Friesen JB,Dahlin JL,Niemitz M,Walters MA,Pauli GF
Abstract : This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other "natural" panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the "natural" label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
|
Displacement of [3H]CP-55,940 from human CB2 receptor expressed in CHO cells incubated for 1 hr by liquid scintillation spectrometry
|
Homo sapiens
|
36.4
nM
|
|
Journal : J Med Chem
Title : The Essential Medicinal Chemistry of Cannabidiol (CBD).
Year : 2020
Volume : 63
Issue : 21
First Page : 12137
Last Page : 12155
Authors : Nelson KM,Bisson J,Singh G,Graham JG,Chen SN,Friesen JB,Dahlin JL,Niemitz M,Walters MA,Pauli GF
Abstract : This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other "natural" panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the "natural" label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
|
Displacement of [3H]CP55940 from rat brain CB1 receptor by scintillation counting method
|
Rattus norvegicus
|
39.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Oxa-adamantyl cannabinoids.
Year : 2021
Volume : 38
First Page : 127882
Last Page : 127882
Authors : Ho TC,Tius MA,Nikas SP,Tran NK,Tong F,Zhou H,Zvonok N,Makriyannis A
Abstract : As a continuation of earlier work on classical cannabinoids bearing bulky side chains we report here the design, synthesis, and biological evaluation of 3'-functionalized oxa-adamantyl cannabinoids as a novel class of cannabinergic ligands. Key synthetic steps involve nucleophilic addition/transannular cyclization of aryllithium to epoxyketone in the presence of cerium chloride and stereoselective construction of the tricyclic cannabinoid nucleus. The synthesis of the oxa-adamantyl cannabinoids is convenient, and amenable to scale up allowing the preparation of these analogs in sufficient quantities for detailed in vitro evaluation. The novel oxa-adamantyl cannabinoids reported here were found to be high affinity ligands for the CB1 and CB2 cannabinoid receptors. In the cyclase assay these compounds were found to behave as potent and efficacious CB1 receptor agonists. Isothiocyanate analog AM10504 is capable of irreversibly labeling both the CB1 and CB2 receptors.
|
Displacement of [3H]CP55940 from mouse CB2 receptor expressed in HEK293 cell membrane by scintillation counting method
|
Mus musculus
|
40.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Oxa-adamantyl cannabinoids.
Year : 2021
Volume : 38
First Page : 127882
Last Page : 127882
Authors : Ho TC,Tius MA,Nikas SP,Tran NK,Tong F,Zhou H,Zvonok N,Makriyannis A
Abstract : As a continuation of earlier work on classical cannabinoids bearing bulky side chains we report here the design, synthesis, and biological evaluation of 3'-functionalized oxa-adamantyl cannabinoids as a novel class of cannabinergic ligands. Key synthetic steps involve nucleophilic addition/transannular cyclization of aryllithium to epoxyketone in the presence of cerium chloride and stereoselective construction of the tricyclic cannabinoid nucleus. The synthesis of the oxa-adamantyl cannabinoids is convenient, and amenable to scale up allowing the preparation of these analogs in sufficient quantities for detailed in vitro evaluation. The novel oxa-adamantyl cannabinoids reported here were found to be high affinity ligands for the CB1 and CB2 cannabinoid receptors. In the cyclase assay these compounds were found to behave as potent and efficacious CB1 receptor agonists. Isothiocyanate analog AM10504 is capable of irreversibly labeling both the CB1 and CB2 receptors.
|
Displacement of [3H]CP55940 from human CB2 receptor expressed in HEK293 cell membrane by scintillation counting method
|
Homo sapiens
|
36.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Oxa-adamantyl cannabinoids.
Year : 2021
Volume : 38
First Page : 127882
Last Page : 127882
Authors : Ho TC,Tius MA,Nikas SP,Tran NK,Tong F,Zhou H,Zvonok N,Makriyannis A
Abstract : As a continuation of earlier work on classical cannabinoids bearing bulky side chains we report here the design, synthesis, and biological evaluation of 3'-functionalized oxa-adamantyl cannabinoids as a novel class of cannabinergic ligands. Key synthetic steps involve nucleophilic addition/transannular cyclization of aryllithium to epoxyketone in the presence of cerium chloride and stereoselective construction of the tricyclic cannabinoid nucleus. The synthesis of the oxa-adamantyl cannabinoids is convenient, and amenable to scale up allowing the preparation of these analogs in sufficient quantities for detailed in vitro evaluation. The novel oxa-adamantyl cannabinoids reported here were found to be high affinity ligands for the CB1 and CB2 cannabinoid receptors. In the cyclase assay these compounds were found to behave as potent and efficacious CB1 receptor agonists. Isothiocyanate analog AM10504 is capable of irreversibly labeling both the CB1 and CB2 receptors.
|
Displacement of [3H]CP55940 from human CB1 receptor transfected in CHO cells measured for 1.5 hrs by liquid scintillation counting analysis
|
Homo sapiens
|
22.0
nM
|
|
|
Displacement of [3H]CP55940 from human CB2 receptor transfected in CHO cells measured for 1.5 hrs by liquid scintillation counting analysis
|
Homo sapiens
|
47.0
nM
|
|
|
Partial agonist activity at human CB1 receptor transfected in CHO cells incubated for 90 mins by scintillation counting based [35S]GTP-gamma-S-binding assay
|
Homo sapiens
|
43.0
nM
|
|
|
Partial agonist activity at human CB2 receptor transfected in CHO cells incubated for 90 mins by scintillation counting based [35S]GTP-gamma-S-binding assay
|
Homo sapiens
|
12.0
nM
|
|
|
Inhibition of human LDHB assessed as reduction in lactate production using pyruvate as substrate at 10 uM in presence of NADH by spectrophotometric analysis relative to control
|
Homo sapiens
|
50.0
%
|
|
|
Antiplasmodial activity against chloroquine-sensitive Plasmodium falciparum NF54
|
Plasmodium falciparum
|
790.0
nM
|
|
|
Antiplasmodial activity against multidrug-resistant Plasmodium falciparum K1
|
Plasmodium falciparum
|
720.0
nM
|
|
