Chemical modification of ring c of himbacine: Discovery of a pharmacophoric element for M2-selectivity

Michael J. Malaska; Abdul H. Fauq; Alan P. Kozikowski; Patricia J. Aagaard; Michael McKinney

doi:10.1016/0960-894X(94)00459-S

Chemical modification of ring c of himbacine: Discovery of a pharmacophoric element for M₂-selectivity

Michael J. Malaska, Abdul H. Fauq, Alan P. Kozikowski, Patricia J. Aagaard, Michael McKinney

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41 Scopus citations

Abstract

Removal of the carbonyl oxygen of himbacine furnishes a molecule which binds with 20-fold and 4-fold lower affinity at the M₂ and M₁ receptor sites, respectively. Thus, the carbonyl oxygen constitutes an important pharmacophoric element responsible for some of the M₂ selectivity of himbacine. Other modifications of the C-ring of the tricyclic portion of himbacine were examined and tested for potency at M₁ and M₂ sites, and the data confirm that M₂ selectivity is optimal with a closed heterocyclic ring and with the presence of a proximal carbonyl oxygen.

Original language	English (US)
Pages (from-to)	61-66
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	5
Issue number	1
DOIs	https://doi.org/10.1016/0960-894X(94)00459-S
State	Published - Jan 5 1995
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/0960-894X(94)00459-S

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title = "Chemical modification of ring c of himbacine: Discovery of a pharmacophoric element for M2-selectivity",

abstract = "Removal of the carbonyl oxygen of himbacine furnishes a molecule which binds with 20-fold and 4-fold lower affinity at the M2 and M1 receptor sites, respectively. Thus, the carbonyl oxygen constitutes an important pharmacophoric element responsible for some of the M2 selectivity of himbacine. Other modifications of the C-ring of the tricyclic portion of himbacine were examined and tested for potency at M1 and M2 sites, and the data confirm that M2 selectivity is optimal with a closed heterocyclic ring and with the presence of a proximal carbonyl oxygen.",

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T2 - Discovery of a pharmacophoric element for M2-selectivity

AU - Malaska, Michael J.

AU - Fauq, Abdul H.

AU - Kozikowski, Alan P.

AU - Aagaard, Patricia J.

AU - McKinney, Michael

PY - 1995/1/5

Y1 - 1995/1/5

N2 - Removal of the carbonyl oxygen of himbacine furnishes a molecule which binds with 20-fold and 4-fold lower affinity at the M2 and M1 receptor sites, respectively. Thus, the carbonyl oxygen constitutes an important pharmacophoric element responsible for some of the M2 selectivity of himbacine. Other modifications of the C-ring of the tricyclic portion of himbacine were examined and tested for potency at M1 and M2 sites, and the data confirm that M2 selectivity is optimal with a closed heterocyclic ring and with the presence of a proximal carbonyl oxygen.

AB - Removal of the carbonyl oxygen of himbacine furnishes a molecule which binds with 20-fold and 4-fold lower affinity at the M2 and M1 receptor sites, respectively. Thus, the carbonyl oxygen constitutes an important pharmacophoric element responsible for some of the M2 selectivity of himbacine. Other modifications of the C-ring of the tricyclic portion of himbacine were examined and tested for potency at M1 and M2 sites, and the data confirm that M2 selectivity is optimal with a closed heterocyclic ring and with the presence of a proximal carbonyl oxygen.

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Chemical modification of ring c of himbacine: Discovery of a pharmacophoric element for M₂-selectivity

Abstract

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