| Synthesis and pharmacology of benzoxazines as highly selective antagonists at M(4) muscarinic receptors. | |
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MedLine Citation:
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PMID: 12086495 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Previously, we reported on PD 102807 (41) as being the most selective synthetic M(4) muscarinic antagonist identified to date. Synthesized analogues of 41 showed no improvement in affinity and selectivity at that time. However, several newly synthesized compounds exhibit a 7-fold higher affinity at M(4) receptors and demonstrate a selectivity of at least 100-fold over all other muscarinic receptor subtypes. For example, compound 28 showed an affinity of pK(i) = 9.00 at M(4) receptors and a selectivity of M(1)/M(4) = 13 183-fold, M(2)/M(4) = 339-fold, M(3)/M(4) = 151-fold, and M(5)/M(4) = 11 220-fold. This high selectivity along with high affinity has not been reported for any synthetic muscarinic antagonist, nor for natural occurring M(4) antagonists such as the M(4) selective Eastern Green Mamba venom MT3 (M(4) pK(b) = 8.7, M(1)/M(4) = 40-fold, M(2)/M(4) > or = 500-fold, M(3)/M(4) > or = 500-fold, and M(5)/M(4) > or = 500-fold). Derivative 24, a compound with a high selectivity pattern as well, has been tested for in vivo efficacy. It was able to block the L-3,4-dihydroxyphenylalanine accumulation produced by CI-1017, an M(1)/M(4) selective muscarinic agonist, in the mesolimbic region and striatum, which suggests that 24 is capable of crossing the blood-brain barrier and confirms the pharmacokinetic data obtained on this compound. This is evidence that suggests that agonist-induced increase in catecholamine synthesis observed in these regions is mediated by M(4) receptors. |
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Authors:
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Thomas M Böhme; Corinne E Augelli-Szafran; Hussein Hallak; Thomas Pugsley; Kevin Serpa; Roy D Schwarz |
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Publication Detail:
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Type: Journal Article |
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: 2002-06-27 Completed Date: 2002-08-02 Revised Date: 2005-11-17 |
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: 3094-102 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. thomas.boehme@aventis.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anthracenes / chemical synthesis*, chemistry, pharmacology Bicyclo Compounds, Heterocyclic / pharmacology Binding, Competitive Biological Availability Blood-Brain Barrier CHO Cells Cricetinae Dihydroxyphenylalanine / biosynthesis Humans Male Motor Activity / drug effects Muscarinic Agonists / pharmacology Muscarinic Antagonists / chemical synthesis*, chemistry, pharmacology Oxazines / chemical synthesis*, chemistry, pharmacology Oximes / pharmacology Rats Rats, Long-Evans Rats, Sprague-Dawley Rats, Wistar Receptor, Muscarinic M1 Receptor, Muscarinic M4 Receptors, Muscarinic / drug effects* Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/9-methoxy-2-propyl-11,12-dihydro-3H,6aH,13H-6-oxa-3,12a-diazabenzo(a)cyclopent(h)anthracene-1-carboxylic acid ethyl ester; 0/Anthracenes; 0/Bicyclo Compounds, Heterocyclic; 0/Muscarinic Agonists; 0/Muscarinic Antagonists; 0/Oxazines; 0/Oximes; 0/Receptor, Muscarinic M1; 0/Receptor, Muscarinic M4; 0/Receptors, Muscarinic; 161774-09-0/PD 142505-0028; 63-84-3/Dihydroxyphenylalanine |
| Comments/Corrections | |
Erratum In:
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J Med Chem 2002 Oct 10;45(21):4800 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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