Studies on Structure-Activity Relation-ships of Guanidine Derivatives. II. : Actions of Aminoethyl-guanidine Derivatives in Adrenergic Mechanisms

Abstract

Pharmacological properties, mainly in adrenergic mechanisms, of several geanethidine analogues were comparatively examined with the following compounds : [2-(hexahydro-1-azepinyl) ethyl] guanidine sulfate (G-7), [2-(1-piperidino) ethyl]guanidine sulfate (G-6), [2-(1-pyrrolidinyl)ethyl]guanidine sulfate (G-5), [2-(diethylamino)ethyl)guanidine sulfate (I), [2-(dipropylamino)ethyl]guanidine sulfate (II), [2-(diisopropylamino)ethyl]guanidine sulfate (III), [2-(dibuthylamino)ethyl]guanidine sulfate (IV), [2-(methylphenylamino)ethyl]guanidine sulfate (V), [2-(diphenylamino)ethyl]guanidine sulfate (VI), [2-(dibenzylamino)ethyl]guanidine sulfate (VII), and [2-(methylcyclohexylamino)ethyl]guanidine sulfate (VIII). The antagonistic action of the compounds against inhibitory effect of adrenergic nerve stimulation on isolated rabbit ileum was examined. The pyrrolidinyl (G-5) and piperidino analogues (G-6) possessed only moderate activities which increased in the hexahydro-1-azepinyl analogue (G-7) and reached a maximum in the eight-membered ring (guanethidine). The compound with the nitrogen atom outside the ring, viz., methylcyclohexylamino analogue (VIII) had a reduced activity. The diethylamino analogue (I) possessed only a moderate activity, which declined with larger dialkylamino analogue (II, III, IV), and the activity was completely lost by replacement of the two alkyl groups with aromatic (VI) or aralkyl (VII) group. Guanethidine, G-7, G-6, G-5, I, and V caused supersensitivity to noradrenaline or adrenaline, and subsensitivity to tyramine in rat blood pressure and cat nictitating membrane, but the activity of VIII was very slight. Furthermore, these compounds also inhibited the contraction of cat nictitating membrane which was elicited by electrical stimulation to preganglionic superior cervical nerve.