Alkaloids indolizidine 235B', quinolizidine 1-epi-207I, and the tricyclic 205B are potent and selective noncompetitive inhibitors of nicotinic acetylcholine receptors.
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 (alpha4beta2, alpha7, alpha3beta2, alpha3beta4, and alpha4beta4). We found that the 5,8-disubstituted indolizidine (-)-235B' acted as a potent noncompetitive blocker of alpha4beta2 nicotinic receptors (IC50 = 74 nM). This effect was highly selective for alpha4beta2 receptors compared with alpha3beta2, alpha3beta4, and alpha4beta4 receptors. The inhibition of alpha4beta2 currents by (-)-235B' was more pronounced as the acetylcholine concentration increased (from 10 nM to 100 microM). Moreover, the blockade of alpha4beta2 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 alpha4beta2 receptors. The quinolizidine (-)-1-epi-207I and the tricyclic (+)-205B had 8.7- and 5.4-fold higher sensitivity, respectively, for inhibition of the alpha7 nicotinic receptor than for inhibition of the alpha4beta2 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.
Tsuneki
Hiroshi
H
Department of Clinical Pharmacology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, 930-0194, Japan. htsuneki@ms.toyama-mpu.ac.jp
You
Yueren
Y
Toyooka
Naoki
N
Kagawa
Syota
S
Kobayashi
Soushi
S
Sasaoka
Toshiyasu
T
Nemoto
Hideo
H
Kimura
Ikuko
I
Dani
John A
JA
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D007212:Indolizines / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D011807:Quinolizines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D014982:Xenopus laevis
C493293:1,2,2a,5,5a,6,7,8,8a-nonahydro-4,6,8-trimethylquinolizino(1,8-ae)pyrrole; C493291:4-(6-heptenyl)-8-methylindolizidine; C493292:4-allyl-8-ethylquinolizidine; D000470:Alkaloids; D006575:Heterocyclic Compounds, 3-Ring; D007212:Indolizines; D018733:Nicotinic Antagonists; D011807:Quinolizines; D011978:Receptors, Nicotinic