Effectiveness of analogs of the kappa opioid receptor antagonist (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) to reduce U50,488-induced diuresis and stress-induced cocaine reinstatement in rats.
BACKGROUND
The kappa opioid receptor (KOR) antagonist, JDTic, was reported to prevent stress-induced reinstatement of cocaine-maintained responding and to have antidepressant-like effects.


OBJECTIVE
Our objectives were to determine whether analogs of JDTic retained KOR antagonist activity and whether an orally effective analog prevented footshock-induced cocaine reinstatement.


METHODS
RTI-194 (i.g. 1-30 mg/kg, s.c. 0.3-10 mg/kg, and i.p. 30 mg/kg), RTI-212 (s.c. 0.3-10 mg/kg and i.p. 30 mg/kg), and RTI-230 (i.g. 3-30 mg/kg and i.p. 1-30 mg/kg) were evaluated for their ability to block diuresis induced by 10-mg/kg U50,488 in rats. RTI-194 was additionally evaluated i.g. (3-100 mg/kg) for its ability to prevent footshock-induced reinstatement of responding previously reinforced with 0.5-mg/kg/inf cocaine.


RESULTS
RTI-194 significantly (p < 0.05) attenuated U50,488-induced diuresis when given i.g., s.c., and i.p. RTI-194s effectiveness increased 1 week following administration. RTI-212 was ineffective. RTI-230 was ineffective when given i.g., but blocked diuresis at 24 h and 8 days (1, 10, and 30 mg/kg), 15 days (10 and 30 mg/kg), 22 and 29 days (30 mg/kg) following i.p. administration. Footshock reinstated responding in vehicle-but not RTI-194 (30 and 100 mg/kg)-treated rats.


CONCLUSIONS
RTI-194 and RTI-230 are effective KOR antagonists, and RTI-194 is now included with JDTic as the only reported compounds capable of antagonizing the KOR following oral administration. The failure of stress to reinstate cocaine seeking in rats treated with RTI-194 is consistent with results reported with JDTic, although it had less efficacy in lowering response levels than JDTic, suggesting a diminished overall effectiveness relative to it.
Beardsley
Patrick M
PM
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA. pbeardsl@vcu.edu
Pollard
Gerald T
GT
Howard
James L
JL
Carroll
F Ivy
FI
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000818:Animals; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004231:Diuresis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D012646:Self Administration; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use
C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; C551454:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)methyl)-2-methylbutyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide dihydrochloride; C551455:N-(1-((4-(3-carbamoylphenyl)-3,4-dimethylpiperidin-1-yl)methyl)-2-methylpropyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; C551456:N-(1-((4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)methyl)-2-methylpropyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; D010880:Piperidines; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer