Document Detail

Synthesis and pharmacology of benzoxazines as highly selective antagonists at M(4) muscarinic receptors.
MedLine Citation:
PMID:  12086495     Owner:  NLM     Status:  MEDLINE    
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.
Thomas M Böhme; Corinne E Augelli-Szafran; Hussein Hallak; Thomas Pugsley; Kevin Serpa; Roy D Schwarz
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  45     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2002 Jul 
Date Detail:
Created Date:  2002-06-27     Completed Date:  2002-08-02     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3094-102     Citation Subset:  IM    
Department of Medicinal Chemistry, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
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MeSH Terms
Anthracenes / chemical synthesis*,  chemistry,  pharmacology
Bicyclo Compounds, Heterocyclic / pharmacology
Binding, Competitive
Biological Availability
Blood-Brain Barrier
CHO Cells
Dihydroxyphenylalanine / biosynthesis
Motor Activity / drug effects
Muscarinic Agonists / pharmacology
Muscarinic Antagonists / chemical synthesis*,  chemistry,  pharmacology
Oxazines / chemical synthesis*,  chemistry,  pharmacology
Oximes / pharmacology
Rats, Long-Evans
Rats, Sprague-Dawley
Rats, Wistar
Receptor, Muscarinic M1
Receptor, Muscarinic M4
Receptors, Muscarinic / drug effects*
Structure-Activity Relationship
Reg. No./Substance:
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
Erratum In:
J Med Chem 2002 Oct 10;45(21):4800

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