Quantitative structure-activity relationships (QSAR) of some 2,2-diphenyl propionate (DPP) derivatives of muscarinic antagonists
QSAR between biological activities and molecular-chemical properties were investigated to aid in designing more effective and potent antimuscarinic pharmacophores. A molecular modeling program was used to calculate geometrical and topological values of a series of DPP pharmacophores. The newly synthesized pharmacophores were tested for their antagonist activities by: (1) inhibition of (N-methyl-/sup 3/H)scopolamine binding assay to the muscarinic receptors of N4TG1 neuroblastoma cells; (2) blocking of acetylcholine-induced contraction of guinea pig ileum; and (3) inhibition of carbachol-induced ..cap alpha..-amylase release from rat pancreas. The differences in the log of these biological activities were directly and significantly related to the distances between the carbonyl oxygen of the DPP and the quaternary nitrogen of the modified pharmacophores. The biological activities, while depending on each particular assay, varied between three and four logs of activity. The charge remained the same in all the pharmacophores. There were no QSAR correlations between molecular volume, molecular connectivity, or principle moments and their antagonistic activities, although multivariate QSAR was not employed. Thus, based on distance geometry, potent muscarinic pharmacophores can be predicted.
- Research Organization:
- Walter Reed Army Institute of Research, Washington, DC
- OSTI ID:
- 6023280
- Report Number(s):
- CONF-870644-
- Journal Information:
- Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Vol. 46:6; Conference: 78. annual meeting of the American Society of Biological Chemists conference, Philadelphia, PA, USA, 7 Jun 1987
- Country of Publication:
- United States
- Language:
- English
Similar Records
Regulation of muscarinic acetylcholine receptors in cultured guinea pig pancreatic acini
Bovine pancreatic polypeptide as an antagonist of muscarinic cholinergic receptors
Related Subjects
ACETYLCHOLINE
BIOCHEMICAL REACTION KINETICS
RECEPTORS
PARASYMPATHOLYTICS
CHEMICAL PROPERTIES
STRUCTURE-ACTIVITY RELATIONSHIPS
AMYLASE
GUINEA PIGS
MATHEMATICAL MODELS
PANCREAS
PROPIONIC ACID
RATS
SMALL INTESTINE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
TUMOR CELLS
AMINES
AMMONIUM COMPOUNDS
ANIMAL CELLS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BODY
CARBOXYLIC ACIDS
DIGESTIVE SYSTEM
DRUGS
ENDOCRINE GLANDS
ENZYMES
ESTERS
GASTROINTESTINAL TRACT
GLANDS
GLYCOSYL HYDROLASES
HYDROLASES
INTESTINES
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
MONOCARBOXYLIC ACIDS
NEUROREGULATORS
O-GLYCOSYL HYDROLASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PARASYMPATHOMIMETICS
PROTEINS
QUATERNARY COMPOUNDS
REACTION KINETICS
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques