Identification and hit-to-lead optimization of a novel class of CB1 antagonists.

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration.

18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self-administration in animal models of addiction. Previously, we proposed that these effects are mediated by the ability of 18-methoxycoronaridine to inhibit nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more potent 18-methoxycoronaridine analogs, we have tested a series of 18-methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293 cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate NR1/NR2B N-methyl-d-aspartate (NMDA) receptors.

Novel chimeric scaffolds to extend the exploration of receptor space: hybrid beta-D-glucose-benzoheterodiazepine structures for broad screening. Effect of amide alkylation on the course of cyclization reactions.

New molecular platforms which are hybrids of two scaffolds-namely, beta-d-glucose and benzodiazepine, each able to bind several proteins-were designed, synthesized and functionalized to serve as probes for broad biological screening. Herein, we describe the syntheses and chemical properties of these novel chimeric scaffolds. Attempted cyclization of the functionalized analogues (-)-96 and (-)-97 afforded the corresponding dimers (-)-98 and (-)-99, respectively, under a variety of reaction conditions, even at concentrations of only 0.

Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents.

Variation of the methoxycarbonyl and C-18 substituents of the antiaddictive compound 18-methoxycoronaridine, and contraction of its isoquinuclidine ring segment, provided 15 congeners for SAR evaluation at opioid and alpha3beta4 nicotinic acetylcholine receptors. The opioid activities were relatively low, and the alpha3beta4 nicotinic acetylcholine receptor activities were found to correlate with in vivo antiaddictive activities.