Non-competitive inhibitory activities of morphinan and morphine derivatives at the alpha 3 beta 4 Neuronal nicotinic acetylcholine receptor determined using nonlinear chromatography and chemometric techniques.
OBJECTIVE
A series of morphine and morphinan derivatives were chromatographed on a column containing immobilized cellular membranes from a cell line expressing the alpha 3 beta 4 neuronal nicotinic acetylcholine receptor (alpha 3 beta 4 nAChR).


METHODS
The results were analyzed using chemometric and molecular modeling techniques in order to predict the noncompetitive inhibitory (NCI) activity of these compounds, the molecular basis for the predicted activity and the binding sites of the inhibitors.


RESULTS
The data demonstrated that seven of seven morphinans were NCIs and bound in the central lumen of the nAChR while only 2 of 13 morphine derivatives had NCI activity and these compounds most likely bound at the quinacrine binding site on the nAChR. The predicted activities were confirmed using functional inhibition studies.


CONCLUSIONS
The results indicate that this approach can be used to rapidly assess pharmacological activity and to guide new drug design.
Jozwiak
Krzysztof
K
Gerontology Research Center, National Institute on Aging/NIH, Baltimore, Maryland 21224-6825, USA.
Moaddel
Ruin
R
Yamaguchi
Rika
R
Maciuk
Alexandre
A
Wainer
Irving W
IW
D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002846:Chromatography, Affinity; D006801:Humans; D008958:Models, Molecular; D009019:Morphinans / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D017711:Nonlinear Dynamics; D011796:Quinacrine / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012414:Rubidium Radioisotopes; D013499:Surface Properties
D009019:Morphinans; D009022:Morphine Derivatives; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; C403530:nicotinic receptor alpha3beta4; D009538:Nicotine; D011796:Quinacrine