Conformationally restricted homotryptamines. Part 6: indole-5-cycloalkyl methylamines as selective serotonin reuptake inhibitors.

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.

Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors.

A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4-9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels.

Conformationally restricted homotryptamines. Part 5: 3-(trans-2-aminomethylcyclopentyl)indoles as potent selective serotonin reuptake inhibitors.

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.

Synthesis and biodistribution of six novel 99mTc complexes of 2-hydroxybenzaldehyde-amino acid Schiff bases.

For the purpose of developing novel diagnostic pharmaceuticals of 99mTc-labeled small-size complexes, six novel complexes of 99mTc-2-hydroxybenzaldehyde-amino acid Schiff bases were designed and synthesized, and their biodistributions in mice were investigated. All the compounds were obtained in radiochemical yields higher than 90% at optimal conditions, and poor uptakes in muscle, brain, heart and tumor were commonly observed with rapid blood clearance. Potentiality was revealed of good kidney imaging by 2-hydroxybenzaldehyde-alanine (L2) complex within 40 min post-injection. Good bone uptake of 2-hydroxybenzaldehyde-histidine (L4) and 2-hydroxybenzaldehyde-aspartic acid (L5) complexes, high spleen accumulation of 2-hydroxybenzaldehyde-glycine (L1) and 2-hydroxybenzaldehyde-cysteine (L3) complexes, and non-specific biodistribution of 2-hydroxybenzaldehyde-glutamic acid (L6) complex were demonstrated.

Enantioselective synthesis of a highly potent selective serotonin reuptake inhibitor. An application of imidazolidinone catalysis to the alkylation of indoles with an alpha,beta-disubstituted alpha,beta-unsaturated aldehyde.

The synthesis of the highly potent and selective serotonin reuptake inhibitor 1 (BMS-594726) is described. In the key construction step, an enantioselective alkylation of the indole nucleus with an alpha-branched alpha,beta-unsaturated aldehyde 7 was accomplished utilizing MacMillan's imidazolidinone catalyst 3b. A rationale is presented for the unexpected stereochemical result, as well as the novel reactivity of the alpha-branched substrate. [reaction: see text]

Adamantyl cannabinoids: a novel class of cannabinergic ligands.

Structure-activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Delta(8)-THC. Our lead compound, (-)-3-(1-adamantyl)-Delta(8)-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.

[Electronic spectral study on salicylaldehyde-amino acid Schiff bases in water].

Seven salicylaldehyde-amino acid Schiff bases in water were investigated by means of electronic spectra, which is helpful to investigate the label of radionuclides with the seven ligands in water for radiopharmaceutical study. Except 10(-5) mol x L(-1) for Sal-tyr, the minimum concentration of formation is 10(-4) mol x L(-1) for all other Sal-aas. Only Sal-his is generated at pH 9-10, while the minimum pH conditions for formation are 8 for Sal-gly and Sal-tyr, and 9 for other four. All Sal-aa but Sal-cys, whose concentration at 36 h is higher than that of newly produced one, decompose gradually since generation, with existing time of 24 h for Sal-gly and Sal-glu, and 48 h for other four.

Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials.

A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.