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 D-2, D-3, and D-4 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 D-3 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 D-3 receptor affinity of 4.3 nM, a 20-fold selectivity for D-3 versus D-2 receptors, and a 300-fold selectivity for D-3 versus D-4 receptors. This compound is predicted to be a useful ligand for studying the functional role of dopamine D-3 receptors in vivo. (C) 2002 Elsevier Science Ltd. All rights reserved.