Synthesis of 2-(5-Bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues and their binding affinities for dopamine D₂, D₃, and D₄ receptors

A series of 2-(5-bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues was prepared and their affinity for dopamine D₂, D₃, and D₄ receptors was measured using in vitro binding assays. The results of receptor binding studies indicated that the incorporation of a pyrrole moiety between the phenyl ring and the basic nitrogen resulted in a significant increase in the selectivity for dopamine D₃ receptors. The most selective compound in this series is 2-(5-bromo-2,3-dimethoxyphenyl)-5-(2-(3-pyridal)piperidinyl)methyl-1H-pyrrole (6p), which has a D₃ receptor affinity of 4.3 nM, a 20-fold selectivity for D₃ versus D₂ receptors, and a 300-fold selectivity for D₃ versus D₄ receptors. This compound is predicted to be a useful ligand for studying the functional role of dopamine D₃ receptors in vivo.