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Pharmacological profiles of a novel α1-adrenoceptor agonist, PNO-49 B, at α1-adrenoceptor subtypes

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Abstract

The effects of a newly synthesized compound, PNO-49B, (R)-(-)-3′-(2-amino-l-hydroxyethyl)-4′-fluo-romethanesulfonanilide hydrochloride, on α1-adrenocepfor subtypes were examined in various tissues in which the following distribution of α1-adrenoceptor subtypes has been suggested: dog carotid artery (α1B), dog mesenteric artery (α1N), rabbit thoracic aorta (α1B + α1L), rat liver (α1B), rat vas deferens (α1A + α1L), rat cerebral cortex (α1A + α1B) and rat thoracic aorta (controversial subtype).

PNO-49 B (0.1–100 μM) produced concentration-dependent contractions in dog mesenteric artery, rabbit thoracic aorta, rat thoracic aorta and rat vas deferens; and the maximal amplitudes of contraction were almost the same as or slighly less than those of noradrenaline. By contrast, the maximal response to PNO-49 B in dog carotid artery was markedly smaller than the response to noradrenaline. In rabbit thoracic aorta, the contractile response to PNO-49 B was not affected by inactivation of the α1B subtype with chloroethylclonidine (CEC), although the response to noradrenaline was attenuated by that treatment. The dissociation constants (KA) of PNO-49 B were not different among the rat thoracic aorta, dog carotid and mesenteric arteries and rabbit thoracic aorta (CEC-pretreated). The contractile responses to PNO-49 B were inhibited competitively by prazosin, HV723 (α-ethyl-3,4,5-trimethoxy-α-(3-((2-(2-methoxy-phenoxy)-ethyl)))-amino(propyl)benzeneacetonitrile fumarate) and by WB4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane). The estimated pA2 values were high for prazosin and WB4101 in rat thoracic aorta and for HV 723 in dog mesenteric artery, whereas the pA2 values for these three antagonists in rabbit thoracic aorta were low and were not altered by pretreatment with CEC. The binding of [3H]-prazosin to membranes prepared from rat vas deferens and liver was inhibited by PNO-49 B in a concentration-dependent manner. The resulting pK1 value for the liver was approximately 1.5 log units lower (one thirtieth in affinity) than the values for the epididymal and prostatic portions of the vas deferens. PNO-49B also inhibited biphasically [3H]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 prejunctional α2-adrenoceptors in rat vas deferens (prostatic portion) nor on the β-adrenoceptors in rat atria. The contractile response to PNO-49 B in rat thoracic aorta was not inhibited by cimetidine, pyrilamine or ketanserin.

These results indicate that PNO-49B is an α1-adrenoceptor agonist with a lower affinity and/or efficacy at the α1B subtype as compared with other α1-subtypes.

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Authors and Affiliations

  1. Department of Pharmacology, Fukui Medical School, 910-11, Matsuoka, Fukui, Japan

    Ikunobu Muramatsu, Tsuyoshi Ohmura & Shigeru Kigoshi

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  1. Ikunobu Muramatsu
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  2. Tsuyoshi Ohmura
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  3. Shigeru Kigoshi
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Muramatsu, I., Ohmura, T. & Kigoshi, S. Pharmacological profiles of a novel α1-adrenoceptor agonist, PNO-49 B, at α1-adrenoceptor subtypes. Naunyn-Schmiedeberg's Arch Pharmacol 351, 2–9 (1995). https://doi.org/10.1007/BF00169057

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