A new look at the neuronal nicotinic acetylcholine receptor pharmacophore
Interest in the field of nicotinic receptors has been recently stimulated both by the discovery of the potential therapeutic effects of new agonists, and by the discovery of an association between nicotinic receptor mutations and human neurological diseases. Expression of human receptors in an exoge...
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| Veröffentlicht in: | European journal of pharmacology 2000-03, Vol.393 (1), p.155-163 |
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| container_title | European journal of pharmacology |
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| creator | Curtis, Logos Chiodini, Florence Spang, Jörg E Bertrand, Sonia Patt, Jörg T Westera, Gerrit Bertrand, Daniel |
| description | Interest in the field of nicotinic receptors has been recently stimulated both by the discovery of the potential therapeutic effects of new agonists, and by the discovery of an association between nicotinic receptor mutations and human neurological diseases. Expression of human receptors in an exogenous system allows their study in isolation. Receptors reconstituted by pairwise injection of either α4 or α3 with β2 or β4 subunits displayed important differences between the resulting receptor subtypes. These results were further compared with those obtained with α3:α4 fusion proteins. The modifications of either the ligand-binding site in the N-terminal domain or in the ionic pore domain were found to affect the pharmacological properties of the receptors. Finally, the analysis of non-natural derivatives of epibatidine demonstrates how an agonist can be modified to be selective at one receptor subtype or to become an antagonist. These data are well explained on the basis of a three-state allosteric model. |
| doi_str_mv | 10.1016/S0014-2999(00)00053-4 |
| format | Article |
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| ispartof | European journal of pharmacology, 2000-03, Vol.393 (1), p.155-163 |
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| subjects | Acetylcholine - pharmacology Acetylcholine receptor Allosteric Regulation Amino Acid Sequence Animals Binding, Competitive Biological and medical sciences Bridged Bicyclo Compounds, Heterocyclic - chemistry Bridged Bicyclo Compounds, Heterocyclic - pharmacology Cell receptors Cell structures and functions Central nervous system Central neurotransmission. Neuromudulation. Pathways and receptors Electrophysiology Fundamental and applied biological sciences. Psychology Humans Ligand binding domain Membrane Proteins - chemistry Membrane Proteins - metabolism Membrane Proteins - physiology Molecular and cellular biology Molecular Sequence Data Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine) Neuron Neurons Nicotinic Agonists - chemistry Nicotinic Agonists - pharmacology Pharmacological Physiological Polymerase Chain Reaction Property Pyridines - chemistry Pyridines - pharmacology Rats Receptors, Nicotinic - drug effects Receptors, Nicotinic - metabolism Receptors, Nicotinic - physiology Recombinant Fusion Proteins - metabolism Sequence Homology, Amino Acid Transfection Vertebrates: nervous system and sense organs Xenopus |
| title | A new look at the neuronal nicotinic acetylcholine receptor pharmacophore |
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