6 beta-acetoxy nortropane and its muscarinic receptor kinetics

Bao gong teng A (BGT-A), a cholinergic tropane, was first separated from Erycibe obtusifolia Benth in China in 1978. 6 beta-Acetoxy nortropane (6 beta-AN), a new tropane analogue of BGT-A, was synthesized in 1983, in our university. Tropanes are generally known as M-cholinoceptor blockers, but 6 beta-AN is a M-cholinoceptor agonist. The levorotatory 6 beta-AN is an active form that has been proved in biological and competitive binding test. The receptor binding experiment of 6 beta-AN were compared with those of M-receptor agonists (oxotremorine, carbachol, BGT-A and pilocarpine) and antagonists (pirenzepine, gallamine, atropine, scopolamine and anisodamine) on 4 different target tissues. The affinity order (pKi) of 6 beta-AN to 4 tissues (heart, cortex-hippocampus, ileal longitudinal muscle and iris) were 7.7, 6.8, 5.6 and 5.5, respectively. 6 beta-AN improved performances of mice in three-arm maze. Down-step tests suggested some potential nootropic effect. 6 beta-AN decreased the heart rate and cardiac contraction, increased the ileal longitudinal muscle contraction and pupil constriction. All above mentioned biological effects were antagonized by atropine. In receptor kinetics studies, we found marked discrepancy between pD2 and pKi. "The stronger the agonist, the larger the difference" suggest that different biological amplification systems are involved. Study on the receptor regulation showed surprisingly a specific subtype receptor regulation and 6 beta-AN gave a downward regulation on M2-R subtype only. Our data show that 6 beta-AN gallamine, oxotremorine and carbachol are M2-R subtype selective agents, while pirenzepine and pilocarpine are M1-R subtype selective agents.