A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain.

Methyllycaconitine (MLA) is the most potent and selective antagonist of the alpha-bungarotoxin sensitive neuronal nicotinic acetylcholine receptor (nAChR). In the present study, an accurate and reproducible technique for the extraction and analysis of MLA from rat plasma and brain is described. This study further sought to determine whether pharmacologically relevant concentrations of MLA could be achieved in brain following peripheral administration. The detection limits for MLA were 0.5 ng/ml for plasma samples and 1.0 ng/g for brain samples. The pharmacokinetic properties of MLA in rat are characterized by a short elimination half-life (19 min) following intravenous (i.v.) administration and poor bioavailability following oral (p.o.) administration. Remarkably, the elimination half-life is significantly longer following p.o. administration (408 min). To assess the extent to which MLA can penetrate into brain, brain and plasma levels of MLA were determined at different time points following intraperitoneal (i.p.) administration of a dose of MLA that produced no observable side effects. Maximal plasma and brain levels were 694 +/- 106 ng/ml and 32 +/- 3 ng/g, respectively. These concentrations are within a range previously reported to selectively block alpha 7 nAChR mediated responses in vitro. Peripherally administered MLA may therefore be a useful tool to further probe the central nervous system functions of the alpha 7 nAChR subunit in vivo.

Synthesis and biological characterization of sqbazide, a novel biotinylated photoaffinity probe for the study of the human platelet thromboxane A2 receptor.

SQBAzide, a biotinylated, azido derivative of the TXA2 receptor antagonist, SQ31,491, was synthesized and characterized. The compound specifically inhibited human platelet aggregation mediated by TXA2 receptor activation and irreversibly labeled platelet TXA2 receptors upon exposure to ultraviolet light. This probe should prove to be of significant value for the study of the receptor-ligand binding domain.