Anticholinergic substances: A single consistent conformation

Abstract

An interactive computer-graphics analysis of 24 antagonists of acetylcholine at peripheral autonomic postganglionic (muscarinic) nervous junctions and at similar junctions in the central nervous system, the crystal structures of which are known, has led to the determination of a single, consistent, energetically favorable conformation for all 24 substances, although their observed crystal structure conformations vary widely. The absolute configuration and the single, consistent (ideal) conformation of the chemical groups required for maximum anticholinergic activity are described quantitatively.

Synthesis and pharmacological effects of new,N-substituted soft anticholinergics based on glycopyrrolate

“…The 2R isomers 2R-SGM and 2R-SGE had pK i values that are in the 8.7-9.5 range; somewhat less than, but close to, those observed for the known highly active antagonists that served as the lead for the present design, N-methylscopolamine and glycopyrrolate (9.2-9.9 and 8.7-9.9, respectively). As expected, the racemic forms, SGM and SGE, showed lower receptor binding affinities than their corresponding 2R isomers (differences significant at P < 0.05 level for M 3 , t-test or nonparametric Mann-Whitney U-test), confirming that stereospecificity is important at these receptors (Barlow et al 1973;Pauling & Datta 1980).…”

“…Because stereospecificity is known to be important at muscarinic receptors, improved anticholinergic activity being obtained with the 2R configuration of glycopyrrolate-type substances (Barlow et al 1973;Pauling & Datta 1980), these soft drug candidates were also prepared starting with optically pure cyclopentylmandelic acid, R(À)1. Racemic 1 was resolved by repeated crystallization of the salts produced between acid 1 and (À)-strychnine (Pavia et al 1988;March 1992).…”

Soft Quaternary Anticholinergics: Comprehensive Quantitative Structure−Activity Relationship (QSAR) with a Linearized Biexponential (LinBiExp) Model

“…48 The obtained almost 10-fold increase is, obviously, a result of an overemphasis resulting from the limited number of data; for a pure enantiomer, one would expect something around a 2-fold increase compared to the isomeric mixture (hence, a corresponding coefficient of only about log 2 ) 0.3) as long as the composition of the enantiomeric mixture is not heavily unbalanced and the isomers do not have opposing effects. It is well-known that stereospecificity is important at these receptors: improved anticholinergic activity is obtained if the absolute configuration of the R 1,2,3substituted carbon is R for most substances (e.g., glycopyrrolate), which because of changes in the priority assignments corresponds to S for atropine and related structures (where R 3 ) CH 2 OH replaces OH), 56,57 and this is nicely confirmed by the present data.…”

Salivatory effects induced by pirenzepine, atropine, metacine and hexamethonium in preganglionar chronically denervated human parotid gland

“…The conformation and spatial orientation of pirenzepine molecules (and probably of its analogue telenzepine) resemble the conformation of 24 known anticholinergic agents which are defined by X-ray structural analysis and other methods (Pauling & Datta 1980;Trummlitz et a1 1984). Though pirenzepine and telenzepine are tricyclic compounds, the above mentioned similarity to the crystalline conformation of the known tricyclic antidepressants, neuroleptics and antihistamine agents is absent.…”