title: 3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism.
abstract: The prototypic cannabinoid type 1 (CB₁) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB₁-selective compounds and explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. Several notable patterns emerged. First, most of the analogs exhibited CB₁ selectivity, with many lacking affinity for the CB₂ receptor. Affinity tended to be better when [³H]5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [³H](-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP55,940), was used as the binding radioligand. Second, many of the analogs produced an agonist-like profile of effects in mice (i.e., suppression of activity, antinociception, hypothermia, and immobility); however, their potencies were not well correlated with their CB₁ binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ⁹-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB₁⁻/⁻ mice, and they failed to stimulate guanosine-5'-O-(3-[³⁵S]thio)-triphosphate binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB₁-selective cannabinoids that produce agonist-like effects in mice through a non-CB₁, non-CB₂ mechanism.
authors.affiliation: RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA. jwiley@rti.org
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: Pinglang
authors.initials: P
authors.lastname: Wang
authors.forename: Rudresha
authors.initials: R
authors.lastname: Kottani
authors.forename: Srinivas
authors.initials: S
authors.lastname: Gadthula
authors.forename: Anu
authors.initials: A
authors.lastname: Mahadeven
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D001892:Camphanes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003511:Cyclohexanols / Q000378:metabolism; D013759:Dronabinol / Q000378:metabolism / Q000494:pharmacology; D054314:Drug Inverse Agonism; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077285:Rimonabant; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D001892:Camphanes; D003511:Cyclohexanols; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant
references.citation: Neuropharmacology. 1995 Jun;34(6):669-76
references.pmid: 7566504
references.citation: Br J Pharmacol. 2005 Jun;145(3):293-300
references.pmid: 15778743
references.citation: Neuroreport. 2001 Jul 20;12(10):2131-6
references.pmid: 11447321
references.citation: Life Sci. 1995;56(23-24):1941-7
references.pmid: 7776817
references.citation: Lancet. 2007 Nov 17;370(9600):1706-13
references.pmid: 18022033
references.citation: J Med Chem. 2002 Jun 20;45(13):2708-19
references.pmid: 12061874
references.citation: Eur J Pharmacol. 1997 Sep 3;334(1):R1-2
references.pmid: 9346339
references.citation: Pharmacol Biochem Behav. 2002 Dec;74(1):31-40
references.pmid: 12376150
references.citation: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5780-5
references.pmid: 10318961
references.citation: J Pharmacol Exp Ther. 1998 Jun;285(3):995-1004
references.pmid: 9618400
references.citation: J Pharmacol Exp Ther. 1995 Oct;275(1):1-6
references.pmid: 7562536
references.citation: Pharmacology. 2002 Oct;66(2):89-99
references.pmid: 12207116
references.citation: Life Sci. 1996;59(8):659-68
references.pmid: 8761016
references.citation: Science. 2005 Oct 14;310(5746):329-32
references.pmid: 16224028
references.citation: Arch Gen Psychiatry. 2001 Apr;58(4):322-8
references.pmid: 11296091
references.citation: FEBS Lett. 1994 Aug 22;350(2-3):240-4
references.pmid: 8070571
references.citation: Neuropharmacology. 2010 Jun;58(8):1215-9
references.pmid: 20214912
references.citation: J Pharmacol Exp Ther. 1993 Apr;265(1):218-26
references.pmid: 8474008
references.citation: J Pharmacol Exp Ther. 2001 Mar;296(3):1013-22
references.pmid: 11181936
references.citation: Bioorg Med Chem Lett. 2010 Jan 1;20(1):26-30
references.pmid: 19954978
references.citation: J Med Chem. 2006 Oct 5;49(20):5969-87
references.pmid: 17004712
references.citation: Science. 1992 Dec 18;258(5090):1946-9
references.pmid: 1470919
references.citation: J Pharmacol Exp Ther. 2000 Oct;295(1):328-36
references.pmid: 10991998
references.citation: J Pharmacol Exp Ther. 1996 May;277(2):586-94
references.pmid: 8627535
references.citation: Chem Phys Lipids. 2002 Dec 31;121(1-2):57-63
references.pmid: 12505690
references.citation: J Pharmacol Exp Ther. 1998 Mar;284(3):1209-17
references.pmid: 9495885
references.citation: Bioorg Med Chem. 2005 Sep 15;13(18):5463-74
references.pmid: 15994087
references.citation: J Med Chem. 1999 Feb 25;42(4):769-76
references.pmid: 10052983
references.citation: Eur J Pharmacol. 2003 Jun 27;471(3):185-93
references.pmid: 12826237
references.citation: Br J Pharmacol. 2008 Jan;153(2):240-51
references.pmid: 18037916
references.citation: Psychopharmacology (Berl). 2004 Dec;177(1-2):35-45
references.pmid: 15167981
references.citation: Psychopharmacology (Berl). 2001 Aug;156(4):410-6
references.pmid: 11498718
references.citation: Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
references.pmid: 4202581
references.citation: J Pharmacol Exp Ther. 1998 Apr;285(1):285-92
references.pmid: 9536023
references.citation: Ann N Y Acad Sci. 2006 Aug;1074:514-36
references.pmid: 17105950
references.citation: Pharmacol Biochem Behav. 1991 Nov;40(3):471-8
references.pmid: 1666911
references.citation: Pharmacol Rev. 2010 Dec;62(4):588-631
references.pmid: 21079038
references.citation: J Pharmacol Exp Ther. 1996 Sep;278(3):989-99
references.pmid: 8819477
references.citation: Mol Pharmacol. 1998 Dec;54(6):1064-72
references.pmid: 9855635