Synthesis and Biological Evaluation of Phenylacetyl Derivatives Having Low Central Nervous System Permeability as Potent and Selective M₂ Muscarinic Receptor Antagonists

抄録

A series of phenylacetyl derivatives containing the 5, 10-dihydro-11H-dibenzo[b, e][1, 4]diazepin-11-one or 5, 11-dihydro-6H-pyrido[2, 3-b][1, 4]benzodiazepin-6-one skeleton was prepared and evaluated for their binding affinities to muscarinic receptors in vitro and for antagonism of bradycardia, salivation and tremor in vivo. Among them, compounds 56 and 66 had high affinity for M₂ muscarinic receptors in the heart (pK_i=8.7 and 8.9, respectively) with low affinity for M₃ muscarinic receptors in the submandibular gland. A structure-activity relationship (SAR) study suggested that the high M₂ selectivity over the M₃ muscarinic receptors of 56 may be attributed to the direction of the carboxamide carbonyl group. In in vivo studies, 56 and 66 antagonized oxotremorine-induced bradycardina in rats on both intravenous and oral administration, and their heart rate increasing effect in dogs with nocturnal bradycardia was about 3-fold greater than that of AF-DX 116. Furthermore, they had almost no influence on oxotremorine-induced tremor in mice, presenting no evidence of central transfer.