Difenidol

Mutschler, E. Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes. 

In vitro tests with the pair 173ajl 73b on the left auricle of guinea pigs resulted also in different intensities of activity. Both compounds were found to lead to a prolongation of the refractory period. However, sila-difenidol exhibits a significant... 

Based on the cyclic-blocking moieties and other substituent groups, subtype-selective muscarinic antagonists can be classified into eight groups (l)tricyclic benzodiazepines, (2) benzothiazepines, (3) quinuclidines, (4) poly-methylene tetramines, (5)indenes, ( 6)sila-difenidols, (7) diphenylacetyloxy derivatives, and (.8) himbacine akaloids. 

From previous investigations it was postulate that muscarinic receptors possess four different subsites for antagonist binding, shown e.g. for the carbinols procyclidine and hexahy-dro-difenidol [43, 44]. Therefore, another aim of this study was to compare the antimuscarinic properties of the enantiomers of the hydroxymethyl-derivatives described above (3, 4, 8, 9) with their related diphenyl- (3a, 4a, 8a, 9a) as well as their dicyclohexyl analogues (3b, 4b, 8b, 9b) in order to interpret their stereoselective interaction witii the dififerent muscarinic receptor subtypes. 

Tetraamines were shown to be competitive antagonists of muscarinic receptors. Melchiorre et al. (1987) presented in J. Med. Chem. the most potent and cardioselective compound of this class, methoctramine (Fig. 2), displaying a selectivity ratio (atria vs. ileum or bladder) of ca. 270. TIPS (1989) showed a picture of muscarinic receptor nomenclature recommended by the Fourth International Symposium on Subtypes of Muscarinic Receptors (Wiesbaden, 1989) where three pharmacologically defined muscarinic subtypes (M1-M3) and five cloned muscarinic subtypes are placed side by side. Among the selective antagonists showed in this classification, p-fluorohexa-hydrosila-difenidol appears (Lambrecht et al., 1989) as a new Mj-selective compound (Fig. 2). In the aforementioned Symposium, Eberlein et al. (1989) presented AF-DX 384 (Fig. 2), a successor of AF-DX 116. 

Lambrecht, G., Feifel, R., Moser, U., Wagner-Rdder, M., Choo, L.K., Camus, J., Tastenoy, M., Waelbroeck, M., Strohmann, C., Tacke, R., Rodrigues de Miranda, J.F., Christophe, J., Mutschler, E., 1989. Pharmacology of hexahydro-difenidol, hexahydro-sila-difenidol and related selective muscarinic antagonists. TIPS, Suppl. 60-64. 

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