Some 2-aryl-5-hydrazino-1,3,4-thiadiazoles have been synthesized and screened for antihypertensive activity. In general, compounds with a 2-substituted phenyl ring had higher activity than their 3- or 4-substituted counterparts or those containing heteroaryl groups. The 2-methylphenyl and 2-ethylphenyl derivatives 7 and 18 were the most potent members of the series. Preliminary studies indicated that the hypotensive action of these compounds was due to a direct relaxant effect on vascular smooth muscle.

Some 2-aryl-5-guanidino-(or N-substituted guanidino)-1,3,4-thiadiazoles and closely related analogues were found to lower blood pressure in metacorticoid (DOCA) hypertensive rats. In the unsubstituted guanidines that exhibited low toxicity, optimum activity resulted when the aryl group was a 2-methylphenyl ring (11). Modifications to the guanidine group did not increase antihypertensive activity, but, in the 2-methylphenyl series, the N-n-butyl- and N-(2-methoxyethyl)guanidines (63 and 78) and the related iminoimidazolidine 93 were of comparable activity to that of the unsubstituted guanidine 11. The iminoimidazolidine 93 showed a somewhat longer duration of action than the guanidine derivatives. Preliminary studies in a pithed rat preparation indicated that these thiadiazole derivatives (11, 63, and 93) lowered blood pressure by a direct relaxant effect on vascular smooth muscle.

1The effects of intravenous administration of the selective m2-adrenoceptor agonists clonidine, UK 14,304 and guanoxabenz on rat pupil diameter were investigated. 2 In rats anaesthetized with pentobarbitone, each agonist produced a marked dose-related increase in pupil diameter; the rank order of potency was: clonidine > UK 14,304 > guanoxabenz. 3 Pretreatment with the selective M2-adrenoceptor antagonist, RX 781094 (0.5 mg/kg, i.v.), produced a parallel 30-40 fold shift to the right of the dose-pupil dilator response curves for the three agonists. Yohimbine (1.5 mg/kg, i.v.) produced about a 10 fold rightward shift of the dose-response curve for guanoxabenz. In contrast, the m1-selective antagonist, prazosin (0.5 mg/kg, i.v.), failed to affect the dose-response relation for guanoxabenz.4 Several antagonists of varying selectivities towards al-and a2-adrenoceptors were tested for their ability to reverse the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). The rank order of potency of the antagonists producing a 50% reversal of this effect was: RX 781094 > yohimbine > piperoxan = rauwolscine > mianserin > RS 21361. Neither corynanthine nor prazosin reversed the guanoxabenz-induced mydriasis. 5Topical application of RX 781094 (0.1 to 3% w/v solutions) onto one eye produced a slow reversal of guanoxabenz-induced mydriasis; the time course and degree of reversal were virtually the same in both eyes. 6 Intracerebroventricular administration of RX781094 (1.25-15 lag total dose) caused a rapid dose-related reversal of the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). 7 Guanoxabenz (0.3 and 1.0 mg/kg, i.v.) did not produce any dilation of the physostigmineconstricted undamaged pupil of the pithed rat. Intravenous adrenaline was found to produce a small mydriatic effect, while atropine completely antagonized the effects of physostigmine in this preparation. 8 These results indicate that M2-adrenoceptor agonists induce mydriasis in the rat through a central aC2-adrenoceptor mechanism. However, the site of action within the central nervous system remains to be determined.

1 Seven a2-adrenoceptor antagonists with diverse chemical structures have been examined for their effects at a2-adrenoceptors in the vas deferens and central nervous system of the rat. 2 Antagonist potency assessed against the presynaptic a2-adrenoceptor agonist action of clonidine in the isolated vas deferens (RX 781094 > Wy 26703 > yohimbine > rauwolscine > piperoxan > mianserin > RS 21361) was highly correlated with the ability of these drugs to displace saturable [3H]-RX 781094 binding from cerebral cortex membranes. 3 Similarly, antagonist potency in the vas deferens was highly correlated with antagonist activity in reversing the centrally-mediated mydriasis induced by the selective a2-adrenoceptor agonist, guanoxabenz, in pentobarbitone-anaesthetized rats. 4 The results indicate that the presynaptic a2-adrenoceptors in the vas deferens are pharmacologically similar to characterized these a2-adrenoceptors in the central nervous system of the rat.

1 Four 2-alkyl (methyl, ethyl, n-propyl and isopropenyl) analogues of idazoxan (RX 781094) vivo, the most favourable substitutions were 2-ethyl (RX 811033) and 2-n-propyl (RX 811054). Compared with yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of guanoxabenz-induced mydriasis in the pentobarbitone-anaesthetized rat. 4 All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine. 5The results indicate that introduction of alkyl groups in the 2-position of idazoxan greatly increases the a2/Ml-adrenoceptor selectivity as measured in binding studies. Improved a2-adrenoceptor affinity and antagonist potency were particularly associated with the 2-ethyl and 2-n-propyl analogues.