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

Rationale The kappa opioid receptor (KOR) antagonist, JDTic, was reported to prevent stress-induced reinstatement of cocaine-maintained responding and to have antidepressant-like effects. Objectives 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