Substituted phenylacetylguanidines: a new class of antihypertensive agents.

The synthesis of a new series of phenylacetylguanidines is described. Several of them exhibited high antihypertensive activity in the rat. The most potent member of the series is N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride [2,6-dichlorophenylacetylguanidine hydrochloride, compound 19], which is now in clinical study under the clinical code number BS 100-141. The structure-activity relationships in this class of compounds are discussed.

Pharmacological actions of the antihypertensive agent N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride (BS 100-141).

Pharmacological properties characterizing N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride (BS 100-141) as a centrally acting antihypertensive agent are described. Its action resembles that of clonidine in many respects but with important differences which are discussed. In DOCA-NaCl--hypertensive conscious rats, BS 100-141 lowers systemic blood pressure with oral doses of 0.3-5 mg/kg. Evidence for a central site of action is provided by the following findings. Infusion of BS 100-141 into the vertebral artery of anaesthetized dogs reduces blood pressure, the same dose being ineffective by i.v. route. Injection into the lateral cerebral ventricle of anaesthetized cats causes a marked reduction in blood pressure and heart rate, the same dose being ineffective when given i.v. The effects of intraventricular injection are inhibited by phentolamine administered by the same route. Intravenous administration of BS 100-141 induces dose-dependent reductions in the splanchnic (sympathetic) nerve activity in the cat. BS 100-141 reduces noradrenaline turnover in the brain stem of the rat as a result of central alpha-adrenoceptor stimulation. Doses which are effective in the hypertensive rat do not reduce dopamine turnover in the corpus striatum. The peripheral, direct alpha-sympathomimetic action of BS 100-141 was demonstrated by the transient increases in blood pressure observed in rats. These increases were unaffected by pretreatment with reserpine, but were antagonized by phentolamine. BS 100-141 was shown to induce contractions of isolated veins and arteries which were competitively inhibited by phentolamine. It stimulates presynaptic cardiac sympathetic alpha-adrenoceptors, thus inhibiting transmitter release to the heart. The sedative effects of BS 100-141 observed in dogs were slight compared to those of clonidine.