Pharmacological effects of some newly developed soft anticholinergics and a receptor-binding QSAR study

Receptor-binding studies using cloned human muscarinic receptors (M1-M4 subtypes) were performed on newly synthesized soft anticholinergics (F-828, F-838, SGM, SGE, SA-A) that are isosteric/ isoelectronic analogs of glycopyrrolate. The receptor binding pK(i) values of the new soft drugs were in the 5.5-9.5 range; with the majority being in the 7.0-8.5 range. As previously observed for similar structures, the pK(i) values tended to decrease with increasing molecular size, and with the introduction of three structural indicator variables, a QSAR equation accounting for close to 75% of the variability could be established. Confirming the known stereospecificity of these receptors, pure 2R isomers were found more active than the corresponding isomeric mixtures. In agreement with soft drug design principles, acid metabolites (SA-A) were found considerably less active than their parent esters. The more active, 2R isomer of SA-A showed some muscarinic subtype selectivity (M3/M2), which was not observed for the parent compounds of this zwitterionic metabolite. Guinea pig ileum assay pA2 values have also been determined, and they were found to be in good agreement with the pK(i), values obtained from the binding study (r2 = 0.72). SGM and SGE caused pupil-dilation in rabbit eyes, but their mydriatic effects lasted considerably shorter than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water-treated eyes, indicating that they are locally active and safe, with a low potential to cause systemic side effects.