PMID: 1971308Jun 1, 1990Paper

trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: a highly potent selective dopamine D1 full agonist

Journal of Medicinal Chemistry
W K BrewsterRichard B Mailman

Abstract

trans-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenan thridine (4a, dihydrexidine) has been found to be a highly potent and selective agonist of the dopamine D1 receptor in rat brain. Dihydrexidine had an EC50 of approximately 70 nM in activating dopamine-sensitive rat striatal adenylate cyclase and a maximal stimulation equal to or slightly greater than that produced by dopamine. Dihydrexidine had an IC50 of 12 nM in competing for [3H]SCH23390 (1a) binding sites in rat striatal homogenate, and of 120 nM versus [3H]spiperone. These data demonstrate that dihydroxidine has about ten-fold selectivity for D1/D2 receptors. More importantly, however, is the fact that dihydrexidine is a full agonist. Previously available agents, such as SKF38393 (1b), while being somewhat more selective for the D1 receptor, are only partial agonists. The isomeric cis-dihydroxybenzo[a]-phenanthridine neither stimulated cAMP synthesis nor inhibited the cAMP synthesis induced by dopamine. The cis isomer also lacked appreciable affinity for [3H]-1a binding sites. N-Methylation of the title compound decreased affinity for D1 sites about 7-8-fold and markedly decreased ability to stimulate adenylate cyclase. Addition of an N-n-propyl group reduced af...Continue Reading

Citations

Apr 1, 1995·Psychopharmacology·V J WattsR B Mailman
Jan 1, 1995·Journal of Neural Transmission. Parkinson's Disease and Dementia Section·M GosselW Danysz
Aug 3, 2005·Psychopharmacology·Mark R Wade, George G Nomikos
Apr 1, 2006·Psychopharmacology·Scott D Gleason, Jeffrey M Witkin
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Feb 5, 2004·Bioorganic & Medicinal Chemistry·Sing-Yuen SitRichard B Mailman
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Feb 16, 2011·Chemical Communications : Chem Comm·Saumen Hajra, Sukanta Bar
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Nov 26, 2008·European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology·Julie A PrzybylaVal J Watts
Jul 22, 2008·Medicinal Research Reviews·Jing ZhangAo Zhang

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