title: Reduction of cocaine self-administration and D3 receptor-mediated behavior by two novel dopamine D3 receptor-selective partial agonists, OS-3-106 and WW-III-55.
abstract: Dopamine D3 receptor (D3R)-selective compounds may be useful medications for cocaine dependence. In this study, we identified two novel arylamide phenylpiperazines, OS-3-106 and WW-III-55, as partial agonists at the D3R in the adenylyl cyclase inhibition assay. OS-3-106 and WW-III-55 have 115- and 862-fold D3R:D2 receptor (D2R) binding selectivity, respectively. We investigated their effects (0, 3, 5.6, or 10 mg/kg) on operant responding by using a multiple variable-interval (VI) 60-second schedule that alternated components with sucrose reinforcement and components with intravenous cocaine reinforcement (0.375 mg/kg). Additionally, we evaluated the effect of OS-3-106 (10 mg/kg) on the dose-response function of cocaine self-administration and the effect of WW-III-55 (0-5.6 mg/kg) on a progressive ratio schedule with either cocaine or sucrose reinforcement. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS-3-106 decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III-55 did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Both compounds reduced locomotion at doses that reduced responding, and both compounds attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior), but neither affected yawning on the descending limb of the 7-OH-DPAT dose-response function (a D2R-mediated behavior). Therefore, both compounds blocked a D3R-mediated behavior. However, OS-3-106 was more effective in reducing cocaine self-administration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine.
authors.affiliation: School of Life Sciences (T.H.C.C., A.L.L., S.M.W., K.N.C., R.F.S., J.L.N.) and Department of Psychology (T.H.C.C., S.M.W., K.N.C., J.D.L., J.L.N.), Arizona State University, Tempe, Arizona; Washington University School of Medicine, St. Louis, Missouri (R.H.M.); and Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas (R.R.L.).
authors.forename: Timothy H C
authors.initials: TH
authors.lastname: Cheung
authors.forename: Amy L
authors.initials: AL
authors.lastname: Loriaux
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Weber
authors.forename: Kayla N
authors.initials: KN
authors.lastname: Chandler
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lenz
authors.forename: Romina F
authors.initials: RF
authors.lastname: Schaan
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Janet L
authors.initials: JL
authors.lastname: Neisewander
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D003042:Cocaine / Q000008:administration & dosage* / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D054333:Drug Partial Agonism; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D001549:Benzamides; D018491:Dopamine Agonists; C585145:OS-3-106; D010879:Piperazines; D050637:Receptors, Dopamine D3; C585146:WW-III-55; D003042:Cocaine
references.citation: Neuropsychopharmacology. 2003 Feb;28(2):329-38
references.pmid: 12589386
references.citation: Behav Pharmacol. 2011 Dec;22(8):773-8
references.pmid: 21979833
references.citation: Brain Res Mol Brain Res. 2003 Mar 17;111(1-2):74-83
references.pmid: 12654507
references.citation: Nat Rev Neurosci. 2004 Jun;5(6):483-94
references.pmid: 15152198
references.citation: Neuropsychopharmacology. 2011 Apr;36(5):1104-13
references.pmid: 21289600
references.citation: Psychopharmacology (Berl). 2000 Oct;152(2):123-31
references.pmid: 11057515
references.citation: Pharmacol Biochem Behav. 2006 Mar;83(3):456-64
references.pmid: 16631246
references.citation: J Pharmacol Exp Ther. 2010 Aug;334(2):556-65
references.pmid: 20494958
references.citation: Ann N Y Acad Sci. 2010 Feb;1187:4-34
references.pmid: 20201845
references.citation: J Med Chem. 2005 Jun 2;48(11):3663-79
references.pmid: 15916415
references.citation: Psychopharmacology (Berl). 2008 Jul;199(1):37-46
references.pmid: 18481046
references.citation: Neuropharmacology. 2009 May-Jun;56(6-7):956-69
references.pmid: 19371586
references.citation: Neuropharmacology. 2005 Sep;49(4):525-41
references.pmid: 15963538
references.citation: Psychopharmacology (Berl). 2008 Nov;201(1):43-53
references.pmid: 18612628
references.citation: Bioorg Med Chem. 2005 Jan 3;13(1):77-87
references.pmid: 15582454
references.citation: Behav Pharmacol. 1997 Feb;8(1):65-74
references.pmid: 9833002
references.citation: Psychopharmacology (Berl). 2007 Aug;193(2):159-70
references.pmid: 17393143
references.citation: J Neurosci. 2002 Nov 1;22(21):9595-603
references.pmid: 12417684
references.citation: Synapse. 2011 Aug;65(8):724-32
references.pmid: 21132811
references.citation: Nature. 1990 Sep 13;347(6289):146-51
references.pmid: 1975644
references.citation: J Neurochem. 1969 Dec;16(12):1609-19
references.pmid: 4314281
references.citation: J Biol Chem. 2012 Mar 16;287(12):8864-78
references.pmid: 22291025
references.citation: Drug Discov Today. 2005 Jul 1;10(13):917-25
references.pmid: 15993811
references.citation: Neuropsychopharmacology. 2003 Jun;28(6):1150-9
references.pmid: 12700684
references.citation: Neuropsychopharmacology. 2006 Jul;31(7):1393-405
references.pmid: 16205781
references.citation: Drug Alcohol Depend. 2006 Jan 4;81(1):63-70
references.pmid: 16005579
references.citation: J Neurosci. 1996 Oct 1;16(19):6100-6
references.pmid: 8815892
references.citation: Behav Pharmacol. 1995 Jun;6(4):333-347
references.pmid: 11224342
references.citation: Psychopharmacology (Berl). 1995 Dec;122(4):351-7
references.pmid: 8657832
references.citation: Neuropharmacology. 2012 Dec;63(8):1346-59
references.pmid: 22960444
references.citation: J Med Chem. 2011 Mar 24;54(6):1555-64
references.pmid: 21348515
references.citation: J Pharmacol Exp Ther. 2007 May;321(2):573-82
references.pmid: 17272677
references.citation: J Comp Psychol. 2002 Sep;116(3):263-9
references.pmid: 12234076
references.citation: J Neurochem. 2003 Nov;87(3):631-41
references.pmid: 14535946
references.citation: Pharmacol Biochem Behav. 2002 Jun;72(3):623-32
references.pmid: 12175459
references.citation: Brain Res Bull. 2003 Oct 15;61(6):595-601
references.pmid: 14519456
references.citation: Brain Res. 1991 Nov 15;564(2):203-19
references.pmid: 1839781
references.citation: FASEB J. 2006 Nov;20(13):2223-33
references.pmid: 17077299
references.citation: J Neurosci Methods. 2009 Jul 30;181(2):241-8
references.pmid: 19467261
references.citation: Psychopharmacology (Berl). 2009 Sep;206(1):73-84
references.pmid: 19513698
references.citation: Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11271-5
references.pmid: 7972046
references.citation: Addict Biol. 2012 Mar;17(2):259-73
references.pmid: 21507153
references.citation: Behav Pharmacol. 2009 Sep;20(5-6):363-79
references.pmid: 19724195
references.citation: Synapse. 2005 Jul;57(1):17-28
references.pmid: 15858839
references.citation: Neuropsychopharmacology. 2004 Aug;29(8):1479-87
references.pmid: 15100700
references.citation: J Pharmacol Exp Ther. 2000 Aug;294(2):680-7
references.pmid: 10900248
references.citation: J Neural Transm Gen Sect. 1993;94(1):11-9
references.pmid: 8129881
references.citation: Nature. 1999 Jul 22;400(6742):371-5
references.pmid: 10432116
references.citation: Neuropsychopharmacology. 2012 Jan;37(1):297-8
references.pmid: 22157862
references.citation: Eur J Neurosci. 2005 Jun;21(12):3427-38
references.pmid: 16026480
references.citation: Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
references.pmid: 4202581
references.citation: Brain Res Mol Brain Res. 1997 May;45(2):335-9
references.pmid: 9149110
references.citation: Neuroscience. 2010 Aug 11;169(1):182-94
references.pmid: 20435100
references.citation: Pharmacol Rev. 1997 Sep;49(3):231-52
references.pmid: 9311022
references.citation: Psychopharmacology (Berl). 2009 Dec;207(3):401-11
references.pmid: 19779699
references.citation: Curr Pharm Des. 2003;9(8):643-71
references.pmid: 12570797
references.citation: J Psychopharmacol. 2011 Feb;25(2):263-73
references.pmid: 20142301
references.citation: Am J Psychiatry. 2005 Aug;162(8):1403-13
references.pmid: 16055761
references.citation: J Pharmacol Exp Ther. 2007 Mar;320(3):1268-78
references.pmid: 17170312
references.citation: J Pharmacol Exp Ther. 2005 Jul;314(1):310-9
references.pmid: 15833897