Dihydrexidine Explained

Dihydrexidine (DAR-0100) is a moderately selective full agonist at the dopamine D₁ and D₅ receptors.^[1] It has approximately 10-fold selectivity for D₁ and D₅ over the D₂ receptor.^[2] Although dihydrexidine has some affinity for the D₂ receptor, it has functionally selective (highly biased) D₂ signaling,^[3] thereby explaining why it lacks D₂ agonist behavioral qualities.^[4]

Dihydrexidine has shown impressive antiparkinson effects in the MPTP-primate model,^[5] and has been investigated for the treatment of Parkinson's disease.^[6] In an early clinical trial the drug was given intravenously and led to profound hypotension so development was halted.^[7] The drug was resurrected when it was shown that smaller subcutaneous doses were safe.^[8] This led to a pilot study in schizophrenia^[9] and current clinical trials to assess its efficacy in improving the cognitive and working memory deficits in schizophrenia and schizotypal disorder.

There have been several reviews of relevance to the compound.^{[10] [11] [12]}

Notes and References

1. Lovenberg TW, Brewster WK, Mottola DM, Lee RC, Riggs RM, Nichols DE, Lewis MH, Mailman RB . Dihydrexidine, a novel selective high potency full dopamine D-1 receptor agonist. . Eur J Pharmacol . 166 . 1 . 111–113 . 1989 . 2572425 . 10.1016/0014-2999(89)90690-0.
2. Mottola DM, Brewster WK, Cook LL, Nichols DE, Mailman RB . Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. . J Pharmacol Exp Ther . 262 . 1 . 383–393 . 1992 . 1352553 .
3. Kilts . JD.. Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs. . J Pharmacol Exp Ther . 301 . 3 . 1179–89 . 2002 . 10.1124/jpet.301.3.1179. 12023553 . etal.
4. ((Darney KJ Jr)), Lewis MH, Brewster WK, Nichols DE, Mailman RB . Behavioral effects in the rat of dihydrexidine, a high-potency, full-efficacy D1 dopamine receptor agonist. . Neuropsychopharmacology . 5 . 3 . 187–195 . 1991 . 1684499 .
5. Taylor JR, Lawrence MS, ((Redmond DE Jr)), Elsworth JD, Roth RH, Nichols DE, Mailman RB . Dihydrexidine, a full dopamine D1 agonist, reduces MPTP-induced parkinsonism in monkeys. . Eur J Pharmacol . 199 . 3 . 389–391 . 1991 . 1680717 . 10.1016/0014-2999(91)90508-N. free .
6. Mailman RB, Nichols DE . Dopamine D1 receptor agonists as antiparkinson drugs. . Trends Pharmacol. Sci. . 19 . 7 . 255–256 . 1998 . 9703756 . 10.1016/S0165-6147(98)01219-X.
7. Blanchet PJ, Fang J, Gillespie M, Sabounjian L, Locke KW, Gammans R, Mouradian MM, Chase TN . Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkinson's disease. . Clin. Neuropharmacol. . 21 . 6 . 339–343 . 1998 . 9844789 .
8. George MS, Molnar CE, Grenesko EL, Anderson B, Mu Q, Johnson K, Nahas Z, Knable M, Fernandes P, Juncos J, Huang X, Nichols DE, Mailman RB . A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia. . Schizophr. Res. . 93 . 1–3 . 42–50 . 2007 . 17467956 . 10.1016/j.schres.2007.03.011. 31375175 .
9. Mu Q, Johnson K, Morgan PS, Grenesko EL, Molnar CE, Anderson B, Nahas Z, Kozel FA, Kose S, Knable M, Fernandes P, Nichols DE, Mailman RB, George MS . A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia. . Schizophr. Res. . 94 . 1–3 . 332–341 . 2007 . 17596915 . 10.1016/j.schres.2007.03.033. 25497605 .
10. Mailman R, Huang X, Nichols DE . Parkinson's disease and D1 dopamine receptors. . Current Opinion in Investigational Drugs . 2 . 11 . 1582–1591 . 2001 . 11763161 .
11. Salmi P, Isacson R, Kull B . Dihydrexidine--the first full dopamine D1 receptor agonist. . CNS Drug Rev. . 10 . 3 . 230–242 . 2004 . 15492773 . 10.1111/j.1527-3458.2004.tb00024.x. 6741759 .
12. Zhang J, Xiong B, Zhen X, Zhang A . Dopamine D1 receptor ligands: where are we now and where are we going. . Med Res Rev . 29 . 2 . 272–294 . 2009 . 18642350 . 10.1002/med.20130 . 25334596 .