Evaluation of benzyltetrahydroisoquinolines as ligands for neuronal nicotinic acetylcholine receptors

1 Effects of derivatives of coclaurine (C), which mimic the 'eastern' or the nonquaternary halves of the alkaloids tetrandrine or d-tubocurarine, respectively, both of which are inhibitors of nicotinic acetylcholine receptors (nACh), were examined on recombinant, human alpha 7, alpha 4 beta 2 and alpha 4 beta 4 nACh receptors expressed in Xenopus oocytes and clonal cell lines using two-electrode voltage clamping and radioligand binding techniques. 2 In this limited series, Cs have higher affinity and are most potent at alpha 4 subunit-containing- nACh receptors and least potent at homomeric alpha 7 receptors, and this trend is very marked for the N-unsubstituted C and its O,O'-bisbenzyl derivative. 3 7-O-Benzyl-N-methylcoclaurine (BBCM) and its 12-O-methyl derivative showed the highest affinities and potencies at all three receptor subtypes, and this suggests that lipophilicity at C7 and/or C12 increases potency. 4 Laudanosine and armepavine (A) were noncompetitive and voltage-dependent inhibitors of alpha 7, alpha 4 beta 2 or alpha 4 beta 4 receptors, but the bulkier C7-benzylated 7BNMC (7-O-benzyl-N-methylcoclaurine) and 7B12MNMC (7-O-benzyl-N,12-O-dimethyl coclaurine) were voltage-independent, noncompetitive inhibitors of nACh receptors. Voltage-dependence was also lost on going from A to its N-ethyl analogue. 5 These studies suggest that C derivatives may be useful tools for studies characterising the antagonist and ion channel sites on human alpha 7, alpha 4 beta 2 or alpha 4 beta 4 nACh receptors and for revealing structure-function relationships for nACh receptor antagonists.