A novel series of [3.2.1] azabicyclic biaryl ethers as alpha3beta4 and alpha6/4beta4 nicotinic receptor agonists.

We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of alpha3- and alpha6-containing nicotinic receptors.

Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity.

Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency.

Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives.

A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.

Null mutant analysis of responses to nicotine: deletion of beta2 nicotinic acetylcholine receptor subunit but not alpha7 subunit reduces sensitivity to nicotine-induced locomotor depression and hypothermia.

The nicotinic acetylcholine receptor (nAChR) subtypes alpha4beta2 and alpha7 comprise the majority of brain nicotine-binding sites. Classical genetic strategies using inbred mice and their hybrids suggest that nicotine's effects on locomotor activity and body temperature are influenced by alpha4beta2 but not alpha7 receptors. To evaluate directly the role of these nicotinic subtypes on responses to nicotine, beta2 and alpha7 null mutant (-/-) mice, as well as wild-type (+/+) and heterozygous (+/-) mice, were tested for baseline body temperature and locomotion and nicotine (0-1.

The beta3 nicotinic receptor subunit: a component of alpha-conotoxin MII-binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors.

Nigrostriatal dopaminergic neurons express many nicotinic acetylcholine receptor (nAChR) subunits capable of forming multiple nAChR subtypes. These subtypes are expressed differentially along the neuron and presumably mediate diverse responses. beta3 subunit mRNA has restricted expression but is abundant in the substantia nigra and ventral tegmental areas.

Variability in response to nicotine in the LSxSS RI strains: potential role of polymorphisms in alpha4 and alpha6 nicotinic receptor genes.

Several studies have shown that genetic factors influence the effects of nicotine on respiration, acoustic startle, Y-maze crosses and rears, heart rate and body temperature in the mouse. Recently, we identified restriction fragment length polymorphisms (RFLPs) associated with the alpha4 (Chrna4) and alpha6 (Chrna6) nicotinic cholinergic receptor genes in the recombinant inbred (RI) strains derived from the Long-Sleep (LS) and Short-Sleep (SS) mouse lines. The alpha4 polymorphism has been identified as a point-mutation at position 529 (threonine to alanine) and the alpha6 polymorphism has not yet been identified.