Summary
YM-12617, 5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxybenzenesulfonamide HCl is a structurally new type of extremely potent α1-adrenoceptor antagonist. Its α-adrenoceptor blocking properties have been compared with those of prazosin, phentolamine and yohimbine using both pharmacological and 3H-ligand binding techniques in vitro and in vivo.
-
1.
In the isolated rabbit aorta, a tissue known to contain mainly α1-adrenoceptors at postjunctional sites, YM-12617 competitively antagonized noradrenaline-induced contraction with a pA2 value of 10.11. Although YM-12617 was also a competitive antagonist toward clonidine at prejunctional α2-adrenoceptors in the isolated rat vas deferens, its affinity for these receptors (pA2=6.41) was 5,000 times lower than that displayed for the postjunctional α1-adrenoceptors in the isolated rabbit aorta.
-
2.
YM-12617 displaced both 3H-WB 4101 and 3H-clonidine binding to rat brain membranes; however, the affinity of YM-12617 for α1-adrenoceptors (pK i=9.64) was 3800 times higher than that for α2-adrenoceptors (pK i-6.06).
-
3.
Based on pA2 values obtained in the isolated tissues and pK i values in the binding assays, YM-12617 was 2–18, 36–117 and 1,740–5,750 times more potent than prazosin, phentolamine and yohimbine in antagonizing α1-adrenoceptors, respectively.
-
4.
In the isolated rabbit pulmonary artery preincubated with 3H-noradrenaline, YM-12617 (1×10−10–1×10−8 M) and prazosin (1×10−9–1×10−7 M) inhibited the stimulation-evoked contaction whereas phentolamine (1×10−8–1×10−6 M) caused not only an inhibition of the evoked contraction but also a facilitation of the evoked 3H-over-flow, suggesting that YM-12617 preferentially blocks postjunctional α-adrenoceptors.
-
5.
In pithed rats, YM-12617 preferentially antagonized the α1-adrenoceptors mediated pressor effect of phenylephrine with a DR10 value of 2.59 μg/kg i.v., although a high dose (3,000 μg/kg i.v.) also inhibited the effect of UK-14,304 at postjunctional α2-adrenoceptors. YM-12617 exhibited an over 1,000-fold selectivity for postjunctional α1-adrenoceptors, in which YM-12617 was 7,210 and 3,540 times more potent than prazosin, phentolamine and yohimbine, respectively.
-
6.
In the isolated rabbit aorta, YM-12617 did not affect the contractile responses to histamine, serotonin, angiotensin II, prostaglandin F2α and KCl at the concentration that completely inhibited the response to phenylephrine.
-
7.
These results demonstrate that YM-12617 is a potent and selective α1-adrenoceptors with a high degree of specificity for these receptors and may be useful for characterizing α-adrenoceptors.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58
Berthelsen S, Pettinger WA (1977) A functional basis for classification of alpha-adrenergic receptors. Life Sci 21:595–606
Borowski E, Starke K, Ehrl H, Endo T (1977) A comparison of pre-and postsynaptic effects of α-adrenolytic drugs in the pulmonary artery of the rabbit. Neurosci 2:285–296
Davey MJ (1980) Relevant features of the pharmacology of prazosin. J Cardiovasc Pharmacol 2 (Suppl 3):S287-S301
Delean A, Munson PJ, Rodbard D (1978) Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol 235:E97-E102
Docherty JR, Starke K (1981) Postsynaptic alpha-adrenoceptor subtype in rabbit blood vessels and rat anococcygeus muscle studied in vitro. J Cardiovasc Pharmacol 3:854–866
Doxey JC, Smith CFC, Walker JM (1977) Selectivity of blocking agents for pre- and postsynaptic alpha-adrenoceptors. Br J Pharmacol 60:91–96
Doxey JC, Roach AG, Smith CFC (1983) Studies on RX 781094: a selective, potent and specific antagonist of α2-adrenoceptors. Br J Pharmacol 78:489–505
Drew GM (1977) Pharmacological characterization of the presynaptic alpha-adrenoceptor in the rat vas deferens. Eur. J Pharmacol 42:123–130
Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muscholl E (eds) Catecholamines. Springer, Berlin Heidelberg New York pp 283–335
Furchgott RF, Bhadrakom S (1953) Reactions of strips of rabbit aorta to epinephrine, isoproterenol, sodium nitrate and other drugs. J Pharamcol Exp Ther 142:39–58
Hammer R, Kobinger W, Pichler L (1980) Binding of an imidazolidine (clonidine), an oxazoloazepin (B-HT 933) and a thiazoloazepin (B-HT 920) to rat brain alpha-adrenoceptors and relation to cardiovascular effects. Eur J Pharmacol 62:227–285
Heinz N, Hofferber (1980) Zur Pharmakologie des α-Rezeptoren-Blockers BE 2254. Arzneim Forsch 30:2135–2139
Hieble JP, Sarau HM, Foley JJ, DeMarinis RM, Pendleton RG (1982) Comparison of central and peripheral alpha 1-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 318:267–273
Kapur H, Mottram DR (1978) A eomparative study on the pre- and postsynaptic alpha blocking activity of a series of benzodioxanes. Biochem Pharmacol 27:1879–1880
Langer SZ (1974) Presynaptic regulation of catecholamine release. Biochem Pharmacol 23:1793–1800
McGrath JC (1982) Evidence for more than one type of postjunctional α-adrenoceptor. Biochem Pharmacol 31:467–484
Mouillé P, Huchet A-M, Chelly J, Lucet BL, Doursout M-F, Schmitt H (1980) Pharmacological properties of AR-C239, 2-[2-[4(o-methoxyphenyl)-piperazine-1-yl]-ethyl]4,4-dimethyl-1,3(2H-4H) isoquinolinedione, a new α-adrenoceptor blocking drug. J Cardiovasc Pharmacol 2:175–191
Starke K (1981) α-Adrenoceptor subclassification. Rev Physiol Biochem Pharmacol 88:199–236
Starke K, Langer SZ (1979) A note on terminology for presynaptic receptors. In: Langer SZ, Starke K, Dubocovich ML (eds) Advances in the biosciences, vol 18, Presynaptic receptors. Pergamon Press, New York, pp 1–3
Starke K, Endo T, Taube HD (1975) Relative pre- and postsynaptic potencies of α-adrenoceptor agonists in the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch Pharmacol 291:55–78
Takenaka T, Shiono K, Honda K, Maeno H (1984a) Preferential blockade of postsynaptic α-adrenoceptor by amosulalol (YM-09538), a new combined α- and β-aderenoceptor blocking agent, in the pulmonary artery of the rabbit. Biogenic Amines 1:285–289
Takenaka T, Honda K, Fujikura T, Niigata K, Tachikawa S, Inukai N (1984b) New sulfamoylphenethylamines, potent α1-adrenoceptor antagonists. J Pharm Pharmacol 30:539–542
Terai M, Takenaka T, Maeno H (1983a) Measurements of pharmacological and 3H-ligand binding in adrenergic receptors. In: Parvez S, Nagatsu T, Nagatsu I, Parvez H (eds) Methods in biogenic amine research. Elsevier/Science Publishers, Amsterdam New York, pp 574–590
Terai M, Usuda S, Kuroiwa I, Noshiro O, Maeno H (1983b) Selective binding of YM-09151-2, a new potent neuroleptic, to D2-dopaminergic receptors. Jpn J Pharmacol 33:749–755
U'Prichard DC, Greenberg DA, Snyder SH (1977) Binding characteristics of a radiolabeled agonist and antagonist at central nervous system alpha-noradrenergic receptors. Mol Pharmacol 13:454–473
U'Prichard DC, Charness ME, Robertson D, Synder SH (1978) Prazosin: differential affinities for two populations of α-noradrenergic receptor binding sites. Eur J Pharmacol 50:87–89
van Meel JCA, de Jonge A, Timmermans PBMWM, van Zwieten (1981) Selectivity of some alpha adrenoceptor agonists for peripheral alpha-1 and alpha-2 adrenoceptors in the normotensive rat. J Pharmcol Exp Ther 219:760–767
van Rossum JM (1963) Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn 143:299–330
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Honda, K., Takenaka, T., Miyata-Osawa, A. et al. Studies on YM-12617: A selective and potent antagonist of postsynaptic α1-adrenoceptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 328, 264–272 (1985). https://doi.org/10.1007/BF00515552
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00515552