Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) with unique binding selectivities and pharmacological activities.
An extended series of alkyl carboxamide analogs of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 1H-pyrazole-3-carboxamide (SR141716; 5) was synthesized. Each compound was tested for its ability to displace the prototypical cannabinoid ligands ([3H]CP-55,940, [3H]2; [3H]SR141716, [3H]5; and [3H]WIN55212-2, [3H]3), and selected compounds were further characterized by determining their ability to affect guanosine 5'-triphosphate (GTP)-gamma-[35S] binding and their effects in the mouse vas deferens assay. This systematic evaluation has resulted in the discovery of novel compounds with unique binding properties at the central cannabinoid receptor (CB1) and distinctive pharmacological activities in CB1 receptor tissue preparations. Specifically, compounds with nanomolar affinity which are able to fully displace [3H]5 and [3H]2, but unable to displace [3H]3 at similar concentrations, have been synthesized. This selectivity in ligand displacement is unprecedented, in that previously, compounds in every structural class of cannabinoid ligands had always been shown to displace each of these radioligands in a competitive fashion. Furthermore, the selectivity of these compounds appears to impart unique pharmacological properties when tested in a mouse vas deferens assay for CB1 receptor antagonism.
Thomas
Brian F
BF
Science and Engineering Group, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Francisco
Maria Elena Y
ME
Seltzman
Herbert H
HH
Thomas
James B
JB
Fix
Scott E
SE
Schulz
Anne-Kathrin
AK
Gilliam
Anne F
AF
Pertwee
Roger G
RG
Stevenson
Leslie A
LA
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000166:cytology; D002462:Cell Membrane / Q000737:chemistry; D003511:Cyclohexanols / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant
D000577:Amides; D003511:Cyclohexanols; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant