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. 2006 Jun 7;10(3):230–242. doi: 10.1111/j.1527-3458.2004.tb00024.x

Dihydrexidine — The First Full Dopamine D1 Receptor Agonist

Peter Salmi 1,✉, Ruben Isacson 1, Björn Kull 1
PMCID: PMC6741759  PMID: 15492773

ABSTRACT

The functional role of dopamine D1 receptors is still controversial. One reason for this controversy is that for a long time the only available agonists for in vivo characterization of dopamine D1 receptors were benzazepines. Among them was the prototype dopamine D1 receptor partial agonist, SKF 38393. The lack of a selective and fully efficacious dopamine D1 receptor agonist hampered basic research on dopamine D1 receptors and left the potential clinical utility of dopamine D1 receptor agonists elusive. The research situation improved when the first potent full dopamine D1 receptor agonist dihydrexidine, a phenanthridine, was introduced in the late 1980s. In contrast to SKF 38393, dihydrexidine was shown to stimulate cyclic AMP synthesis just as well or better than dopamine, and potently displaced [3H]SCH 23390 from rat and monkey striatal membranes. Also, dihydrexidine was the first dopamine D1 receptor agonist that had potent antiparkinsonian activity in a primate model of Parkinson's disease. This finding suggested clinical utility for dopamine D1 receptor agonists in Parkinson's disease and that this utility might be critically dependent on the intrinsic efficacy of the drug. Clinical utility for dopamine D1 receptor agonists in other central nervous disorders might also be dependent on the intrinsic efficacy of the drug. However, even though studies with dihydrexidine as a pharmacological tool have pointed to the clinical use for dopamine D1 receptor agonists, dihydrexidine's unfavorable pharmacokinetic profile and various adverse effects are likely to restrict or even preclude its use in humans. This review article provides an updated overview of the pharmacology of dihydrexidine and discusses possible clinical utility of dopamine D1 receptor agonists in various central nervous system disorders.

Keywords: Dopamine, Dopamine agonist, Dopamine D1 receptor agonist, Dihydrexidine

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