Anticholinergics structure-activity relationships

Compounds of this type of structure exhibit a stronger anticholinergic and a weaker histaminolytic activity than the corresponding free bases112 The same structure-activity relationship is found for analogous carbon systems. Compounds of type 155 exhibit in contrast to their carbon analogue only a short duration of activity (because of hydrolytic inactivation), which is even shorter than that of the basic sila-benzhydrylethers themselves. 

With respect to the acid moiety of the anticholinergics, the following structure-activity relationships are found ... 

Nichols DE Studies ofthe relationship between molecular structure and hallucinogenic activity. Pharmacol Biochem Behav 24 335-340, 1986 Nichols DE Hallucinogens. Pharmacol Ther 101 131-191, 2004 Peroutka SJ Serotonin receptors, in Psychopharmacology The Third Generation of Progress. Edited by Meltzer HY. New York, Raven, 1987, pp 303-311 Perry PJ, Wilding OC, Juhl RP Anticholinergic psychosis. Am J Hosp Pharm 35 725— 728, 1978... 

Diaryl derivatives with a hydroxyl group at another site in the alkylene chain are represented by BRL 14342 (78). Some structural relationship with (76) and (77) may be seen in this compound, which is currently undergoing tolerance and EEG studies in human volunteers. The results suggest that (78) is a potent nondepressant CNS-active drug [220]. The compound is a 60 40 mixture of the two possible diastereoisomers (racemates ), which are of approximately equal activity [220]. It is stated that the (-)-isomer shows fewer peripheral anticholinergic effects than the (+)-form. The (+)-isomer is more active than the (—)-isomer in the reserpine reversal test at low doses, but the 2 isomers have rou Iy equal effects in tests on prevention of reserpine-induced hypothermia [221]. Because (78) has 2 chiral centres it is not clear if the optically active compounds are single diastereoisomers or mixtures of 2 of them. 

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