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Abstract: Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET. [Copyright &y& Elsevier]

Abstract: A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding. [Copyright &y& Elsevier]

Abstract: A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose–response similar to the SSRI fluoxetine in microdialysis studies in rats. [Copyright &y& Elsevier]

Abstract: Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds. [Copyright &y& Elsevier]

Abstract: A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT. [Copyright &y& Elsevier]

Abstract: A series of N,N-dimethylhomotryptamines was prepared and their binding affinities at the serotonin transporter (SERT) were determined. Compounds possessing an electron withdrawing substituent at the C5-position of the indole nucleus were found to be potent SSRIs. Initial attempts at conformational restriction of the propylamine sidechain by incorporation of a quinuclidine bicyclic structure did not improve binding affinity at SERT. [Copyright &y& Elsevier]