| Abstract
| - The dopamine D3 receptor is recognized as a potential therapeutic target for the treatment ofvarious neurological and psychiatric disorders. Targetting high affinity and D3 versus D2receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variationsin the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines withmarkedly improved affinity and selectivity. Molecular modeling studies supported the structuraldevelopment. Pharmacophore models for dopamine D2 and D3 receptor ligands were developedfrom their potentially bioactive conformation and were compared in order to get insight intomolecular properties of importance for D2/D3 receptor selectivity. For the 72 compoundspresented here, an extended and more linear conformation in the aliphatic or aryl spacersturned out to be crucial for dopamine D3 receptor selectivity. Structural diversity in the arylmoiety (benzamides, heteroarylamides, arylimides) had a major influence on (sub)nanomolarD3 receptor affinity, which was optimized with more rigid aryl acrylamide derivatives.Compound 38 (ST 280, (E)-4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoylamide) displayed a most promising pharmacological profile (Ki (hD3) = 0.5 nM; Ki (hD2L) =76.4 nM; selectivity ratio of 153), and above that, compound 38 offered the prospect of a novelradioligand as a pharmacological tool for various D3 receptor-related in vitro and in vivoinvestigation.
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