| dc.description.abstract | 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 a7, a4b2 and a4b4 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 a4 subunit-containing-nACh
receptors and least potent at homomeric a7 receptors, and this trend is very marked for the
N-unsubstituted C and its O,O0-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 a7,
a4b2 or a4b4 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 a7, a4b2 or a4b4 nACh receptors and for revealing
structure–function relationships for nACh receptor antagonists. | |
