Title

Evaluation Of Benzyltetrahydroisoquinolines As Ligands For Neuronal Nicotinic Acetylcholine Receptors

Department

neurobiology

Document Type

Article

Abstract

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 α7, α4β2 and α4β4 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 α4 subunit-containing-nACh receptors and least potent at homomeric α7 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 α7, α4β2 or α4β4 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 α7, α4β2 or α4β4 nACh receptors and for revealing structure-function relationships for nACh receptor antagonists. © 2005 Nature Publishing Group All rights reserved.

Publication Date

12-1-2005

Publication Title

British Journal of Pharmacology

ISSN

00071188

Volume

146

Issue

1

First Page

15

Last Page

24

Digital Object Identifier (DOI)

10.1038/sj.bjp.0706307

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