Medication discovery for addiction: translating the dopamine D3 receptor hypothesis.
The dopamine D3 receptor (D3R) has been investigated as a potential target for medication development to treat substance use disorders (SUDs) with a particular focus on cocaine and methamphetamine. Currently, there are no approved medications to treat cocaine and methamphetamine addiction and thus developing pharmacotherapeutics to complement existing behavioral strategies is a fundamental goal. Novel compounds with high affinity and D3R selectivity have been evaluated in numerous animal models of drug abuse and favorable outcomes in nonhuman primate models of self-administration and relapse have provided compelling evidence to advance these agents into the clinic. One approach is to repurpose drugs that share the D3R mechanism and already have clinical utility, and to this end buspirone has been identified as a viable candidate for clinical trials. A second, but substantially more resource intensive and risky approach involves the development of compounds that exclusively target D3R, such as GSK598809 and PG 619. Clinical investigation of these drugs or other novel D3R-selective agents will provide a better understanding of the role D3R plays in addiction and whether or not antagonists or partial agonists that are D3R selective are effective in achieving abstinence in this patient population.
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, MD 21224, USA.
Amy Hauck
AH
Newman
Brandi L
BL
Blaylock
Michael A
MA
Nader
Jack
J
Bergman
David R
DR
Sibley
Phil
P
Skolnick
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008694:Methamphetamine / Q000009:adverse effects; D015394:Molecular Structure; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D019966:Substance-Related Disorders / Q000188:drug therapy*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3; D008694:Methamphetamine; D003042:Cocaine