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Structure‐activity studies of N,N‐dialkyl and cycloalkyl carbamate esters of dimethylethanolamine and choline with nicotinic and muscarinic cholinergic properties
Author(s) -
Saraswati Manda,
LernerMarmarosh Nicole,
Wang David X.,
Sheu SheyShing,
Sharma Viranda,
Abood Leo G.
Publication year - 1994
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430310209
Subject(s) - muscarinic acetylcholine receptor , nicotinic agonist , muscarinic antagonist , chemistry , muscarinic acetylcholine receptor m3 , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m1 , nicotinic antagonist , cholinergic , acetylcholine receptor , muscarinic acetylcholine receptor m5 , receptor , biochemistry , endocrinology , biology
Structure‐activity studies were performed on a series of newly synthesized N‐sub‐stituted carbamate esters of choline and dimethylethanolamine which exhibited either or both nicotinic and muscarinic cholinergic properties. Substitutions on the carbamyl N consisted of varying lengths of dialkyls, diphenyl, and various heterocycles. The compounds were evaluated for their nicotinic and muscarinic receptor binding properties in rat brain membranes, their effect on muscarinic receptor‐activated phosphoinositide (PI) turnover in rat cortical slices, and for muscarinic receptor‐mediated intracelluar Ca release in a mouse adrenal carcinoma cell line transfected with an m1 muscarinic cholinergic receptor gene. N,N‐diethylcarbamylcholine had the highest affinity for nicotinic cholinergic receptors; the K i value of 1 × 10 −9 M approached that of nicotine and being 1/5 that for the dimethyl analogue. With increasing chain length of the dialkyl substituents the nicotinic affinity progressively decreased, while muscarinic affinity increased. N,N‐diphenylcarbamylcholine had a K i value of 1 × 10 −7 M for nicotinic receptors and exhibited nicotinic antagonist activity. Contrary to the results with [ 3 H]‐N‐methylcarbamylcholine binding, the tertiary derivatives exhibited higher K i values for [ 3 H]‐3‐quinuclidinyl benzilate binding than the quarternaries; the tertiary dibutyl and diphenyl had the highest affinities with K i values of 4 × 10 −7 M. The inhibition of muscarinic receptor‐mediated PI turnover and release of intracellular calcium were related to the muscarinic antagonist potency of the compounds. © 1994 Wiley‐Liss, Inc.