Novel benzofuran derivatives with dual 5-HT1A receptor and serotonin transporter affinity.

Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.

Synthesis, potency, and in vivo evaluation of 2-piperazin-1-ylquinoline analogues as dual serotonin reuptake inhibitors and serotonin 5-HT1A receptor antagonists.

On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.

Studies toward the discovery of the next generation of antidepressants. Part 6: Dual 5-HT1A receptor and serotonin transporter affinity within a class of arylpiperazinyl-cyclohexyl indole derivatives.

Based on the previously reported discovery lead, 3-(cis-4-(4-(1H-indol-4-yl)piperazin-1-yl)cyclohexyl)-5-fluoro-1H-indole (2), a series of related arylpiperazin-4-yl-cyclohexyl indole analogs were synthesized then evaluated as 5-HT transporter inhibitors and 5-HT(1A) receptor antagonists. The investigation of the structure-activity relationships revealed the optimal pharmacophoric elements required for activities in this series. The best example from this study, 5-(piperazin-1-yl)quinoline analog (trans-20), exhibited equal binding affinities at 5-HT transporter (K(i)=4.9nM), 5-HT(1A) receptor (K(i)=6.2nM) and functioned as a 5-HT(1A) receptor antagonist.

Studies toward the discovery of the next generation of antidepressants. Part 5: 3,4-Dihydro-2H-benzo[1,4]oxazine derivatives with dual 5-HT1A receptor and serotonin transporter affinity.

The design, synthesis, and structure-activity relationship of two novel classes of benzoxazine derivatives with dual selective serotonin reuptake inhibitors and 5-HT(1A) receptor activities are described.

Studies towards the next generation of antidepressants. Part 4: derivatives of 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine with affinity for the serotonin transporter and the 5-HT1A receptor.

Derivatives of the serotonin reuptake inhibitor 4-(5-fluoro-1H-indol-3-yl)cyclohexylamine, in which serotonin 1A (5-HT(1A)) receptor pharmacophoric elements are incorporated, are reported. Analogs exhibiting affinity for both the serotonin transporter and the 5-HT(1A) receptor are described. Compounds containing 1-(4-indolyl)piperazine and 2-(1H-indol-4-yloxy)ethylamine are promising leads for further SAR studies.