Evaluation of benzyltetrahydroisoquinolines as ligands for neuronal nicotinic acetylcholine receptors

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 α 7, α 4 β 2 and α 4 β 4 nACh receptors expressed in Xenopus oocytes and clonal cell lines using two‐electrode voltage clamping and radioligand binding techniques. In this limited series, Cs have higher affinity and are most potent at α 4 subunit‐containing‐nACh receptors and least potent at homomeric α 7 receptors, and this trend is very marked for the N‐ unsubstituted C and its O,O′‐ bisbenzyl derivative. 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. Laudanosine and armepavine (A) were noncompetitive and voltage‐dependent inhibitors of α 7, α 4 β 2 or α 4 β 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. These studies suggest that C derivatives may be useful tools for studies characterising the antagonist and ion channel sites on human α 7, α 4 β 2 or α 4 β 4 nACh receptors and for revealing structure–function relationships for nACh receptor antagonists.British Journal of Pharmacology (2005) 146 , 15–24. doi: 10.1038/sj.bjp.0706307