Neuromedicinal chemistry of 5-HT1A-receptor agonists and antagonists

Recent progress in a project aiming at developing selective 5-HT1A-receptor agonists and antagonists is reviewed. A large number of analogues of 8-OH-DPAT has been synthesized, and throughout, we have attempted to prepare enantiopure derivatives. Modifications have been concentrated to the N-alkyl substituents, and substitutions in the C1, C2 and C3-positions. The synthetic strategies and procedures are discussed. A number of interesting observations have been made. Affinity, efficacy and stereoselectivity are modified by the various substitutions. The results have been used to deduce a 3D-model for 5-HT1A-receptor agonists. Recently, Pd-catalyzed reactions have been utilized to prepare a number of pharmacologically interesting analogues of 8-OH-DPAT with various C8-substituents. We have also succeeded to convert the agonist 8-OH-DPAT into an antagonist by introduction of a C5-fluoro substituent, producing (S)-UH-301. The pharmacology of this selective 5-HT1A-receptor antagonist is discussed.