Scott D Gleason1, Jeffrey M Witkin. 1. Psychiatric Drug Discovery, Neuroscience Discovery Research, The Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
Abstract
RATIONALE: The full D1 receptor agonist dihydrexidine (DHX) [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson's disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. METHODS: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D1 receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D1 agonist, fenoldopam, was evaluated. RESULTS: SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958<ABT-431<SKF 75670A<or=dinapsoline<SKF 81297<DHX. Fenoldopam (10 and 30 mg/kg) did not substitute and was without effect on rates of responding. CONCLUSIONS: DHX produces prominent dopamine D1 receptor agonist effects in vivo and is likely to produce subjective effects in humans similar to other D1 receptor agonists.
RATIONALE: The full D1 receptor agonist dihydrexidine (DHX) [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson's disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. METHODS: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D1 receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D1 agonist, fenoldopam, was evaluated. RESULTS: SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958<ABT-431<SKF 75670A<or=dinapsoline<SKF 81297<DHX. Fenoldopam (10 and 30 mg/kg) did not substitute and was without effect on rates of responding. CONCLUSIONS:DHX produces prominent dopamine D1 receptor agonist effects in vivo and is likely to produce subjective effects in humans similar to other D1 receptor agonists.
Authors: T W Lovenberg; W K Brewster; D M Mottola; R C Lee; R M Riggs; D E Nichols; M H Lewis; R B Mailman Journal: Eur J Pharmacol Date: 1989-07-04 Impact factor: 4.432