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 Î±7, Î±4Î²2 and Î±4Î²4 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 Î±4 subunit-containing-nACh receptors and least potent at homomeric Î±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 Cl2 increases potency. Laudanosine and armepavine (A) were noncompetitive and voltage-dependent inhibitors of Î±7, Î±4Î²2 or Î±4Î²4 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 Î±7, Î±4Î²2 or Î±4Î²4 nACh receptors and for revealing structure-function relationships for nACh receptor antagonists. Â© 2005 Nature Publishing Group All rights reserved.
British Journal of Pharmacology
Digital Object Identifier (DOI)
Exley, Richard; Iturriaga-VÃsquez, Patricio; Lukas, Ronald J.; Sher, Emanuele; Cassels, Bruce K.; and Bermudez, Isabel, "Evaluation Of Benzyltetrahydroisoquinolines As Ligands For Neuronal Nicotinic Acetylcholine Receptors" (2005). Translational Neuroscience. 220.