Dihydrexidine — The First Full Dopamine D₁ Receptor Agonist

Abstract

The functional role of dopamine D(1) 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 D(1) receptors were benzazepines. Among them was the prototype dopamine D(1) receptor partial agonist, SKF 38393. The lack of a selective and fully efficacious dopamine D(1) receptor agonist hampered basic research on dopamine D(1) receptors and left the potential clinical utility of dopamine D(1) receptor agonists elusive. The research situation improved when the first potent full dopamine D(1) 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 [(3)H]SCH 23390 from rat and monkey striatal membranes. Also, dihydrexidine was the first dopamine D(1) receptor agonist that had potent antiparkinsonian activity in a primate model of Parkinson's disease. This finding suggested clinical utility for dopamine D(1) 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 D(1) 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 D(1) 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 D(1) receptor agonists in various central nervous system disorders.

Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist

“…This mutant localized to the plasma membrane like WT (Figure S5A) and was activated by DA with similar potency to WT D1R (pEC 50 = 6.2 and 6.4, D1R(I183C) and WT D1R, respectively; Figure S5B). In addition, the synthetic D1-like receptor partial agonist SKF38393 76 similarly activated WT D1R and D1R(I183C) (Figures S5C–E). Thus, the introduction of cysteine at position I183 did not substantially alter receptor function.…”

Dopamine D1 receptor ligands: Where are we now and where are we going

“…[138][139][140][141][142][143] Several compounds have already been under development. These include: (1) benzazepine analogues: CEE-03-310 (37) by Addex for the treatment of drug abuse in 2002, TSR-1938 (38) by CeNes for the treatment of substance abuse and sleep disorders in 2003, Ecopipam (9, SCH-39166) by Schering-Plough for the management of obesity in 2000, and (2) polycyclic derivatives: DHX (27a) by Purdue University for drug dependence, PD and schizophrenia, DAR-201 (dinapsoline, 32a) by DarPharm Inc as treatment for PD, schizophrenia (þ)-32a by Bristol-Myers Squibb under development for treatment of PD, and Doxanthrine (35a) by Purdue University as anti-psychotics and as antiparkinsonian agent.…”

D1/D2-dopamine receptor agonist dihydrexidine stimulates inspiratory motor output and depresses medullary expiratory neurons

“…4F, and 5). Based on what is known concerning postsynaptic inhibition linked to activation of D2Rs (5,28), it seems to be linked to suppressed adenylyl cyclase and reduced cAMP production (40). Similar transduction mechanisms affect excitability in medullary Aug-E neurons of the cat, because intracellular injection of cAMP-PKA inhibitors evokes MP hyperpolarization and effects on action potential properties (38) that are comparable to those of DHD in this study.…”

“…This meant a high probability of relating effects to D1R activation and to functional selectivity mediated by adenylyl cyclase and cyclic AMP upregulation (29). Since then, the D1:D2 selectivity has been downgraded to ϳ10 -12:1 (4,15,29,30,40), and weak D3R (49) as well as ␣ 2 (28) receptor agonist affinity have been reported.…”