| Synthesis and pharmacological characterization of novel analogues of the nicotinic acetylcholine receptor agonist (+/-)-UB-165. | |
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MedLine Citation:
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PMID: 12109907 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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(+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2, alpha3beta4, and alpha7). The first class of compounds comprises the three pyridine isomers 4-6, corresponding to the 3-, 2-, and 4-substituted pyridine isomers, respectively. Deschloro UB-165 (4) displayed a 2-3-fold decrease in affinity at alpha4beta2 and alpha3beta4 nAChR subtypes, as compared with (+/-)-UB-165, while at the alpha7 subtype a 31-fold increase in affinity was observed. At each of the nAChR subtypes, high affinity binding was dependent on the presence of a 3-substituted pyridine, and the other isomers, 5 and 6, resulted in marked decreases in binding affinities. The second class of compounds is based on replacing the pyridyl unit of 1 with a diazine moiety, giving pyridazine (7), pyrimidine (8), and pyrazine (9), which retain the "3-pyridyl" substructure. Modest reductions in binding affinity were observed for all of the diazine ligands at all nAChR subtypes, with the exception of 7, which retained potency comparable to that of 4 in binding to alpha7 nAChR. In functional assays at the alpha3beta4 nAChR, all analogues 4-9 were less potent, as compared with 1, and the rank order of functional potencies correlated with that of binding potencies. Computational studies indicate that the 3-substituted pyridine 4 and 2-substituted pyridine 5, as well as the diazine analogues 7-9, all conform to a distance-based pharmacophore model recently proposed for the alpha4beta2 receptor. However, the nicotinic potencies of these ligands vary considerably and because 5 lacks appreciable nicotinic activity, it is clear that further refinements of this model are necessary in order to describe adequately the structural and electronic demands associated with this nAChR subtype. This rational series of compounds based on UB-165 presents a systematic approach to defining subtype specific pharmacophores. |
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Authors:
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Christopher G V Sharples; Gunter Karig; Graham L Simpson; James A Spencer; Emma Wright; Neil S Millar; Susan Wonnacott; Timothy Gallagher |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 45 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2002 Jul |
Date Detail:
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Created Date: 2002-07-11 Completed Date: 2002-08-12 Revised Date: 2010-06-04 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 3235-45 Citation Subset: IM |
Affiliation:
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Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Binding, Competitive Brain / metabolism Bridged Compounds / chemical synthesis*, chemistry, metabolism Cell Line Ligands Molecular Conformation Monte Carlo Method Neurons / metabolism Nicotinic Agonists / chemical synthesis*, chemistry, metabolism Pyrazines / chemical synthesis, chemistry, metabolism Pyridazines / chemical synthesis, chemistry, metabolism Pyridines / chemical synthesis*, chemistry, metabolism Pyrimidines / chemical synthesis, chemistry, metabolism Radioligand Assay Rats Receptors, Nicotinic / drug effects, metabolism Stereoisomerism Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/(2-chloro-5-pyridyl)-9-azabicyclo(4.2.1)non-2-ene; 0/Bridged Compounds; 0/Ligands; 0/Nicotinic Agonists; 0/Pyrazines; 0/Pyridazines; 0/Pyridines; 0/Pyrimidines; 0/Receptors, Nicotinic; 0/alpha7 nicotinic acetylcholine receptor; 0/nicotinic receptor alpha3beta4; 0/nicotinic receptor alpha4beta2; 289-95-2/pyrimidine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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