PHARMACOLOGICAL PROFILES OF A NOVEL ALPHA(1)-ADRENOCEPTOR AGONIST, PNO-49B, AT ALPHA(1)-ADRENOCEPTOR SUBTYPES

The effects of a newly synthesized compound, PNO-49B, mino-1-hydroxyet hyl)-4'-fluoromethanesulfonanilide hydrochloride, on alpha(1)-adrenoce ptor subtypes were examined in various tissues in which the following distribution of alpha(1)-adrenoceptor subtypes has been suggested: dog carotid artery (alpha(1B)), dog mesenteric artery (alpha(1N)), rabbit thoracic aorta (alpha(1B) + alpha(1L)), rat liver (alpha(1B)), rat va s deferens (alpha(1A) + alpha(1L)), rat cerebral cortex (alpha(1A) + a lpha(1B)) and rat thoracic aorta (controversial subtype). PNO-49B (0.1 -100 mu M) produced concentration-dependent contractions in dog mesent eric artery, rabbit thoracic aorta, rat thoracic aorta and rat vas def erens; and the maximal amplitudes of contraction were almost the same as or slightly less than those of noradrenaline. By contrast, the maxi mal response to PNO-49B in dog carotid artery was markedly smaller tha n the response to noradrenaline. In rabbit thoracic aorta, the contrac tile response to PNO-49B was not affected by inactivation of the alpha (1B) subtype with chloroethylclonidine (CEC), although the response to noradrenaline was attenuated by that treatment. The dissociation cons tants (K-A) of PNO-49B were not different among the rat thoracic aorta , dog carotid and mesenteric arteries and rabbit thoracic aorta, dog c arotid and mesenteric arteries and rabbit thoracic aorta (CEC-pretreat ed). The contractile responses to PNO-49B were inhibited competitively by prazosin, HV723 y-phenoxy)-ethyl)-amino(propyl)benzeneacetonitrile fumarate) and by WB4101 ethoxyphenoxyethyl)-aminomethyl-1,4-benzodiox ane). The estimated pA(2) values were high for prazosin and WB4101 in rat thoracic aorta and for HV723 in dog mesenteric artery, whereas the pA(2) values for these three antagonists in rabbit thoracic aorta wer e low and were not altered by pretreatment with CEC. the binding of [H -3]-prazosin to membranes prepared from rat vas deferens and liver was inhibited by PNO-49B in a concentration-dependent manner. The resulti ng pK(1) value for the liver was approximately 1.5 log units lower (on e thirtieth in affinity) than the values for the epididymal and prosta tic portions of the vas deferens. PNO-49B also inhibited biphasically [H-3]prazosin binding to prazosin-high affinity sites of rat cerebral cortex membranes, and the low but high affinity sites for PNO-49B was abolished by CEC-pretreatment. PNO-49B had no effect on the prejunctio nal alpha(2)-adrenoceptors in rat vas deferens (prostatic portion) nor on the beta-adrenoceptors in rat atria. The contractile response to P NO-49B in rat thoracic aorta was not inhibited by cimetidine, pyrilami ne or ketanserin. These results indicate that PNO-49B is an alpha(1)-a drenoceptor agonist with a lower affinity and/or efficacy at the alpha (1B) subtypes as compared with other alpha(1)-subtypes.