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Bioorg Med Chem Lett. 2005 Dec 15;15(24):5567-73. Epub 2005 Oct 10.

Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs.

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Neuroscience Discovery, Abbott GmbH & Co. KG, D-67008 Ludwigshafen, Germany.


Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.

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