title: Design and synthesis of systemically active metabotropic glutamate subtype-2 and -3 (mGlu2/3) receptor positive allosteric modulators (PAMs): pharmacological characterization and assessment in a rat model of cocaine dependence.
abstract: As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure-activity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu2 receptor PAMs and no activity at mGlu3. Compound optimization led to the identification of potent mGlu2/3 selective PAMs with no in vitro activity at mGlu1,4-8 or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu2 and PAM activity at mGlu3. The most potent mGlu2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu2/3 PAMs. On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu2/3 receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.
authors.affiliation: Cell Death and Survival Networks Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute , 10901 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Raveendra-Panickar
authors.initials: RP
authors.lastname: Dhanya
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Melinda
authors.initials: M
authors.lastname: Davis
authors.forename: Pooi San
authors.initials: PS
authors.lastname: Lee
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Hilary Highfield
authors.initials: HH
authors.lastname: Nickols
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.forename: Manoranjan S
authors.initials: MS
authors.lastname: D'Souza
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Andre
authors.initials: A
authors.lastname: Der-Avakian
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3
references.citation: J Pharmacol Exp Ther. 1999 Oct;291(1):161-70
references.pmid: 10490900
references.citation: Annu Rev Pharmacol Toxicol. 1997;37:205-37
references.pmid: 9131252
references.citation: Mol Pharmacol. 2006 Aug;70(2):616-26
references.pmid: 16645124
references.citation: Curr Drug Targets. 2012 Jan;13(1):145-56
references.pmid: 21777188
references.citation: J Med Chem. 2005 May 19;48(10):3605-12
references.pmid: 15887967
references.citation: J Med Chem. 1999 Mar 25;42(6):1027-40
references.pmid: 10090786
references.citation: Trends Pharmacol Sci. 2009 Jan;30(1):25-31
references.pmid: 19058862
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4170-5
references.pmid: 15753323
references.citation: J Med Chem. 2012 Nov 26;55(22):9434-45
references.pmid: 23009245
references.citation: Neuropharmacology. 2013 Mar;66:114-21
references.pmid: 22445601
references.citation: J Pharmacol Exp Ther. 2011 Jan;336(1):165-77
references.pmid: 20947638
references.citation: Adv Exp Med Biol. 2002;513:197-223
references.pmid: 12575822
references.citation: Neuropharmacology. 2013 Mar;66:40-52
references.pmid: 22640631
references.citation: CNS Drugs. 2010 Aug;24(8):669-93
references.pmid: 20658799
references.citation: Neuropsychopharmacology. 2010 Sep;35(10):2021-36
references.pmid: 20555310
references.citation: Behav Brain Res. 2006 Oct 2;173(1):148-52
references.pmid: 16834996
references.citation: Nat Rev Drug Discov. 2005 Feb;4(2):131-44
references.pmid: 15665858
references.citation: J Pharmacol Exp Ther. 2002 Nov;303(2):608-15
references.pmid: 12388642
references.citation: Bioorg Med Chem Lett. 2005 Mar 15;15(6):1565-71
references.pmid: 15745798
references.citation: J Pharmacol Exp Ther. 2002 Jan;300(1):162-71
references.pmid: 11752112
references.citation: Neuropharmacology. 2013 Mar;66:1-11
references.pmid: 22564439
references.citation: Bioorg Med Chem Lett. 2004 Nov 1;14(21):5329-32
references.pmid: 15454221
references.citation: Curr Med Chem. 2012;19(9):1269-76
references.pmid: 22338563
references.citation: J Neurochem. 2000 Sep;75(3):889-907
references.pmid: 10936169
references.citation: J Med Chem. 2004 Aug 26;47(18):4595-9
references.pmid: 15317469
references.citation: Brain Res. 2010 Dec 2;1363:180-90
references.pmid: 20875805
references.citation: Brain Res. 2012 Sep 14;1473:161-72
references.pmid: 22820300
references.citation: Adv Pharmacol. 2011;62:37-77
references.pmid: 21907906
references.citation: Bioorg Med Chem Lett. 2009 May 1;19(9):2524-9
references.pmid: 19328692
references.citation: J Neurosci. 2004 May 19;24(20):4723-7
references.pmid: 15152032
references.citation: J Neurosci. 2007 Aug 22;27(34):9077-85
references.pmid: 17715344
references.citation: J Neurosci. 2007 Aug 1;27(31):8297-308
references.pmid: 17670976
references.citation: Brain Res. 2004 Sep 3;1019(1-2):246-54
references.pmid: 15306259
references.citation: Neurobiol Dis. 2012 Jul;47(1):75-91
references.pmid: 22472187
references.citation: J Pharmacol Exp Ther. 1999 Jul;290(1):112-20
references.pmid: 10381766
references.citation: Bioorg Med Chem Lett. 2010 Jan 1;20(1):175-9
references.pmid: 19932615
references.citation: Psychopharmacology (Berl). 2006 Jun;186(2):143-9
references.pmid: 16703399
references.citation: J Med Chem. 2012 Feb 23;55(4):1445-64
references.pmid: 22148748
references.citation: Brain Res Brain Res Rev. 1999 Jan;29(1):83-120
references.pmid: 9974152
references.citation: Bioorg Med Chem Lett. 2005 Sep 15;15(18):4068-72
references.pmid: 16005222
references.citation: J Pharmacol Exp Ther. 2006 Jul;318(1):173-85
references.pmid: 16608916
references.citation: Eur J Pharmacol. 2009 Jan 28;603(1-3):62-72
references.pmid: 19046965
references.citation: Neuropsychopharmacology. 2008 Jul;33(8):1818-26
references.pmid: 17895914
references.citation: J Med Chem. 2009 Jul 23;52(14):4115-8
references.pmid: 19469556
references.citation: J Med Chem. 2010 Dec 23;53(24):8775-9
references.pmid: 21105727
references.citation: Mol Pharmacol. 2008 Apr;73(4):1213-24
references.pmid: 18171729
references.citation: J Med Chem. 2011 Jan 13;54(1):342-53
references.pmid: 21155570
references.citation: ACS Chem Neurosci. 2011 Aug 17;2(8):382-93
references.pmid: 22860167
references.citation: J Pharmacol Exp Ther. 2001 Aug;298(2):453-60
references.pmid: 11454905
references.citation: Trends Pharmacol Sci. 2004 May;25(5):265-72
references.pmid: 15120493
references.citation: J Pharmacol Exp Ther. 2006 Aug;318(2):922-31
references.pmid: 16675638
references.citation: J Med Chem. 2003 Jul 17;46(15):3189-92
references.pmid: 12852748
references.citation: Neuropharmacology. 2012 Jan;62(1):322-31
references.pmid: 21855555
references.citation: Neurosci Res. 1998 Jan;30(1):65-82
references.pmid: 9572581
references.citation: Bioorg Med Chem Lett. 2005 May 2;15(9):2389-93
references.pmid: 15837331