Parallel synthesis and dopamine D3/D2 receptor screening of novel {4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}carboxamides

We have applied a fast and high-yielding method for the parallel amidation of 4-[4-(2-methoxyphenyl)piperazin-1-yl]butylamine yielding analogs of the partial dopamine receptor agonist BP 897. Using this amino scaffold prepared in solution and polymer-bound carboxylic acid equivalents, we have synthesized a series of high affinity dopamine D-3 receptor ligands. The novel compounds were obtained in good to excellent yield and purity. Biological evaluation included determination of binding affinities at hD(2S) and hD(3) receptor subtypes. From the 22 novel structures presented here, compound 4v showed high affinity (K-i (hD3) 1.6 nM) and a 136-fold preference for the D-3 receptor versus that for the D-2 receptor subtype. Our results suggest that this derivatization technique is a useful method to speed up structure-activity relationships studies on dopamine receptor subtype modulators. (c) 2005 Elsevier Ltd. All rights reserved.