THE [(METHYLOXY)IMINO]METHYL MOIETY AS A BIOISOSTER OF ARYL - A NOVELCLASS OF COMPLETELY ALIPHATIC BETA-ADRENERGIC-RECEPTOR ANTAGONISTS

Previous studies in the field of beta-adrenergic drugs had supported t he hypothesis of the existence of a bioisosterism between the [(methyl eneamino)oxy]methyl moiety (C=NOCH2, MAOMM) of type B beta-blocking dr ugs and the aryl (Ar) of type A beta-blocking agents. In the MAOMM, ho wever, the carbon of the CH2 linked to the oximic oxygen possesses a h ybridization (sp(3)) and a geometry different from those of the corres ponding carbon of Ar which possesses an sp(2) hybridization. Furthermo re, in the MAOMM, in its preferred conformation, the unsaturated porti on (C=N) is situated in a spatial area which does not correspond exact ly to the area occupied by Ar. The formal inversion of the atomic sequ ence C=NOCH2 of the MAOMM leads to a different type of group, the [(me thyloxy)imino] methyl moiety (CH2ON=C, MOIMM), which, in the E configu ration, appears to present greater steric and electronic analogies wit h an Ar, with respect to the MAOMM. On the basis of these observations , some completely aliphatic (E)-N-(3-amino-2-hydroxypropylidene) (alky loxy)amino derivatives of type C (11a,b and 12a,b) were synthesized, t he their beta-adrenergic properties were compared with those of the co rresponding [(methyleneamino)oxy]methyl isomers of type B (19a,b and 2 0a,b). The similar beta-adrenergic properties of 11,12 and 19,20 evalu ated in vitro both by radioligand binding assays and by functional tes ts on isolated preparations, are discussed on the basis of considerati ons regarding the spatial correspondences and electronic analogies bet ween the MOIMM and the MAOMM.