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Alkaloids Indolizidine 235B', Quinolizidine 1-epi-207I, and the Tricyclic 205B are Potent and Selective Noncompetitive Inhibitors of Nicotinic Acetylcholine Receptors

Department of Clinical Pharmacology (H.T., Y.Y., S.Ka., S.Ko., T.S., I.K.) and Faculty of Pharmaceutical Sciences (N.T., H.N.), Toyama Medical and Pharmaceutical University, Toyama, Japan, and Division of Neuroscience, Baylor College of Medicine, Houston, Texas (J.A.D.)

Nicotinic acetylcholine receptors are key molecules in cholinergic transmission in the nervous system. Because of their structural complexity, only a limited number of subtype-specific agonists and antagonists are available to study nicotinic receptor functions. To overcome this limitation, we used voltageclamp recordings to examine the effects of several frog skin alkaloids on acetylcholine-elicited currents in Xenopus laevis oocytes expressing major types of neuronal nicotinic receptors (42, 7, 32, 34, and 44). We found that the 5,8-disubstituted indolizidine (-)-235B' acted as a potent noncompetitive blocker of 42 nicotinic receptors (IC₅₀ = 74 nM). This effect was highly selective for 42 receptors compared with 32, 34, and 44 receptors. The inhibition of 42 currents by (-)-235B' was more pronounced as the acetylcholine concentration increased (from 10 nM to 100 µM). Moreover, the blockade of 42 currents by (-)-235B' was voltage-dependent (more pronounced at hyperpolarized potentials) and use-dependent, indicating that (-)-235B' behaves as an open-channel blocker of this receptor. Several other 5,8-disubstituted indolizidines (5-n-propyl-8-n-butylindolizidines), two 5,6,8-trisubstituted indolizidines ((-)-223A and (+)-6-epi-223A), and a 1,4-disubstituted quinolizidine ((+)-207I) were less potent than (-)-235B', and none showed selectivity for 42 receptors. The quinolizidine (-)-1-epi-207I and the tricyclic (+)-205B had 8.7- and 5.4-fold higher sensitivity, respectively, for inhibition of the 7 nicotinic receptor than for inhibition of the 42 receptor. These results show that frog alkaloids alter the function of nicotinic receptors in a subtype-selective manner, suggesting that an analysis of these alkaloids may aid in the development of selective drugs to alter nicotinic cholinergic functions.

Received for publication March 25, 2004.

Accepted for publication July 6, 2004.

Address correspondence to: Hiroshi Tsuneki, Department of Clinical Pharmacology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: htsuneki{at}ms.toyama-mpu.ac.jp

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