Structure-activity studies of N,N-dialkyl and cycloalkyl carbamate esters of dimethylethanolamine and choline with nicotinic and muscarinic cholinergic properties

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 ³H]-N-methylcarbamylcholine binding, the tertiary derivatives exhibited higher K_i values for ³H]-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.