Dopamine Receptor Pharmacology

Dopamine Receptor Pharmacology

1. Definition & overview

• Dopamine (DA) is a catecholamine neurotransmitter consisting of a catechol moiety (3,4-dihydroxyphenyl) linked to an ethylamine side chain; it is the predominant catecholamine in the CNS and the immediate biosynthetic precursor of norepinephrine (NE) and epinephrine (EPI) (G&G 14e Ch.15, p.295; Ch.14, p.295).
• Dopamine receptors are a family of five distinct G protein-coupled receptors (GPCRs) — D₁, D₂, D₃, D₄, D₅ — encoded by separate genes and grouped, on structural, signalling and pharmacological grounds, into two subfamilies: D1-like (D₁, D₅) and D2-like (D₂, D₃, D₄) (G&G 14e Ch.15, p.297; KDT 8e Ch.31, p.453).
• DA is a polar molecule that does not readily cross the blood-brain barrier (BBB) — a fact central to therapeutics: parenteral DA has no central effect, and Parkinson's disease (PD) is treated with the BBB-permeant precursor l-DOPA (levodopa) rather than DA itself (G&G 14e Ch.15, p.295; Ch.14, p.296; KDT 8e Ch.31, p.452).
• DA is closely related to melanin (formed by oxidation of DA, tyrosine, or l-DOPA), which gives the substantia nigra ("black substance") its dark colour. Non-enzymatic oxidation of DA and l-DOPA generates cytotoxic reactive oxygen species (ROS) and quinones; DA- and dopa-quinones form adducts with α-synuclein, a major constituent of Lewy bodies in PD — linking DA metabolism to neurodegeneration (G&G 14e Ch.15, p.295).
• Pharmacological agents acting at DA receptors are central to the treatment of PD, schizophrenia, bipolar disorder, hyperprolactinaemia, restless leg syndrome (RLS), Huntington's disease, ADHD, Tourette's syndrome, nausea/vomiting, and shock/heart failure — making dopamine receptor pharmacology one of the highest-yield CNS topics (G&G 14e Ch.15, p.297; KDT 8e Ch.32, p.463).
• Highest DA concentrations are in the brain, but peripheral DA stores exist in the adrenal medulla, the plexuses of the GI tract / enteric nervous system, and the renal proximal tubule (where DA is locally synthesised and acts as a paracrine/autocrine natriuretic) (G&G 14e Ch.15, p.295; Ch.14, p.296).