title: Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands.
abstract: BACKGROUND
  Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity.
  
  
  RESULTS
  Novel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC50 values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response.
  
  
  CONCLUSIONS
  Our results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects in vivo. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
authors.forename: Haitao
authors.initials: H
authors.lastname: You
authors.forename: Vinicius M
authors.initials: VM
authors.lastname: Gadotti
authors.forename: Ravil R
authors.initials: RR
authors.lastname: Petrov
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.forename: Philippe
authors.initials: P
authors.lastname: Diaz
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology; D002243:Carbolines / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000700:Analgesics; D020747:Calcium Channels, T-Type; D002227:Carbazoles; D002243:Carbolines; D008024:Ligands; C574055:NMP144 compound; C574054:NMP4 compound; C574056:NMP7 compound; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
references.citation: Brain Res Rev. 2009 Apr;60(1):84-9
references.pmid: 19162069
references.citation: Bioorg Med Chem. 2003 Mar 6;11(5):717-22
references.pmid: 12538001
references.citation: Br J Pharmacol. 2009 Mar;156(5):740-50
references.pmid: 19226289
references.citation: Br J Pharmacol. 2011 Jan;162(2):428-40
references.pmid: 20880025
references.citation: Bioorg Med Chem Lett. 2009 Aug 1;19(15):4299-302
references.pmid: 19505824
references.citation: Mol Pharmacol. 1995 Sep;48(3):443-50
references.pmid: 7565624
references.citation: J Neurophysiol. 2004 Dec;92(6):3562-74
references.pmid: 15317842
references.citation: J Med Chem. 2009 Jan 22;52(2):433-44
references.pmid: 19115816
references.citation: Pharmacol Rev. 2002 Jun;54(2):161-202
references.pmid: 12037135
references.citation: Neurosci Lett. 1995 Feb 17;186(2-3):91-4
references.pmid: 7777206
references.citation: Channels (Austin). 2010 Nov-Dec;4(6):518-22
references.pmid: 21164281
references.citation: Eur J Neurosci. 2004 Nov;20(9):2311-20
references.pmid: 15525273
references.citation: Pain. 1992 Oct;51(1):5-17
references.pmid: 1454405
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3093-8
references.pmid: 15705714
references.citation: Pain. 2010 Nov;151(2):337-344
references.pmid: 20696525
references.citation: Biochem J. 1991 Oct 1;279 ( Pt 1):129-34
references.pmid: 1718258
references.citation: EMBO J. 2001 Dec 17;20(24):7033-40
references.pmid: 11742980
references.citation: Br J Pharmacol. 2008 Jan;153(2):390-401
references.pmid: 17994110
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11268-73
references.pmid: 21690417
references.citation: Eur J Neurosci. 2003 Jun;17(12):2750-4
references.pmid: 12823482
references.citation: Neurobiol Dis. 1998 Dec;5(6 Pt B):447-61
references.pmid: 9974177
references.citation: Trends Pharmacol Sci. 2004 Sep;25(9):465-70
references.pmid: 15559248
references.citation: J Neurosci. 2005 Mar 9;25(10):2530-6
references.pmid: 15758162
references.citation: Br J Pharmacol. 2008 Dec;155(7):1104-16
references.pmid: 18846037
references.citation: Eur J Pharmacol. 2001 Mar;415(2-3):141-9
references.pmid: 11274992
references.citation: J Neurosci. 1995 Oct;15(10):6552-61
references.pmid: 7472417
references.citation: Nature. 1993 Sep 2;365(6441):61-5
references.pmid: 7689702
references.citation: Psychopharmacology (Berl). 1996 Jul;126(2):125-31
references.pmid: 8856831
references.citation: Handb Exp Pharmacol. 2005;(168):1-51
references.pmid: 16596770
references.citation: Pharmacol Res. 2011 Jul;64(1):60-7
references.pmid: 21440630
references.citation: J Neurochem. 2005 Oct;95(2):437-45
references.pmid: 16086683
references.citation: Br J Pharmacol. 2010 Jun;160(3):561-73
references.pmid: 20233215
references.citation: Proc Natl Acad Sci U S A. 1992 May 1;89(9):3825-9
references.pmid: 1315042
references.citation: J Pharmacol Exp Ther. 1999 Nov;291(2):618-26
references.pmid: 10525080
references.citation: J Membr Biol. 2002 Jun 1;187(3):225-38
references.pmid: 12163980
references.citation: Drug Discov Today. 2006 Aug;11(15-16):708-16
references.pmid: 16846798
references.citation: EMBO J. 2005 Jan 26;24(2):315-24
references.pmid: 15616581
references.citation: J Biol Chem. 2005 Feb 18;280(7):5129-32
references.pmid: 15590622
references.citation: Anesthesiology. 2007 Apr;106(4):787-94
references.pmid: 17413917
references.citation: Mol Pharmacol. 2010 Feb;77(2):211-7
references.pmid: 19864434
references.citation: Eur J Pharmacol. 1980 Oct 17;67(2-3):313-6
references.pmid: 6893963
references.citation: Pain. 1987 Jul;30(1):103-114
references.pmid: 3614974
references.citation: Channels (Austin). 2010 Nov-Dec;4(6):510-7
references.pmid: 21150297
references.citation: Comb Chem High Throughput Screen. 2008 Jul;11(6):420-6
references.pmid: 18673270
references.citation: J Neurosci. 2009 Oct 21;29(42):13106-14
references.pmid: 19846698
references.citation: J Biol Chem. 2008 Jun 6;283(23):16124-34
references.pmid: 18390906
references.citation: J Med Chem. 2002 Aug 1;45(16):3509-23
references.pmid: 12139462
references.citation: Pharmacol Rev. 2010 Dec;62(4):588-631
references.pmid: 21079038
references.citation: Neuroscience. 2005;135(1):235-45
references.pmid: 16084654
references.citation: Nature. 1990 Aug 9;346(6284):561-4
references.pmid: 2165569
references.citation: Pain. 2001 Sep;93(3):239-245
references.pmid: 11514083