Document Detail

trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: a highly potent selective dopamine D1 full agonist.
MedLine Citation:
PMID:  1971308     Owner:  NLM     Status:  MEDLINE    
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 affinity for D1 sites by about 50-fold and essentially abolished the ability to stimulate adenylate cyclase. However, this latter derivative had twice the affinity of the D2-selective agonist quinpirole for the D2 receptor. The results are discussed in the context of a conceptual model for the agonist state of the D1 receptor.
W K Brewster; D E Nichols; R M Riggs; D M Mottola; T W Lovenberg; M H Lewis; R B Mailman
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  33     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1990 Jun 
Date Detail:
Created Date:  1990-06-28     Completed Date:  1990-06-28     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1756-64     Citation Subset:  IM    
Department of Medical Chemistry and Pharmacognosy, School of Pharmacy and Pharmacol Sciences, Purdue University, West Lafayette, Indiana 47907.
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MeSH Terms
Adenylate Cyclase / metabolism*
Computer Simulation
Dopamine Agents / chemical synthesis*,  metabolism,  pharmacology
Molecular Conformation
Phenanthridines / chemical synthesis*,  pharmacology
Receptors, Dopamine / drug effects*,  metabolism
Receptors, Dopamine D1
Receptors, Dopamine D2
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Dopamine Agents; 0/Phenanthridines; 0/Receptors, Dopamine; 0/Receptors, Dopamine D1; 0/Receptors, Dopamine D2; 123039-93-0/dihydrexidine; EC Cyclase

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