Vasorelaxation by new hybrid compounds containing dihydropyridine and pinacidil-like moieties / Yagupolskii L.M., Antepohl W., Artunc F., Handrock R., Klebanov B.M., Maletina I.I., Marxen B., Petko K.I., Quast U., Vogt A., Weiss C., Zibold J., Herzig S. // Journal of Medicinal Chemistry. - 1999. - V. 42, l. 25. - P. 5266-5271.

ISSN:

00222623

Type:

Article

Abstract:

The synthesis and pharmacological properties of a novel type of vasorelaxant hybrid compounds are described. The investigated compounds originate from fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel blockers, and/or from fluorinated analogues of pinacidil, which is an opener of ATP-sensitive potassium channels. In particular, we studied the most potent hybrid, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2- difluoromethoxy-5-N-(N'-cyano-N'-1,2,2-trimethyl-propylguanidyl)-phenyl)-1,4- dihydropyridine (4a), together with its parent compounds, the dihydropyridine 1b and the pinacidil analogue 3. In isolated rat mesenteric arteries, micromolar concentrations of 4a relaxed contractions exerted by K+- depolarization or by norepinephrine. The latter effect was sensitive to the potassium channel blocker glibenclamide. Micromolar 4a also inhibited [3H](+)-isradipine and [3H]P1075 binding to rat cardiac membranes, and it blocked L-type calcium channels expressed in a mammalian cell line. The respective parent compounds lb and 3 were always more potent and more selective regarding calcium channel or potassium channel interaction, respectively. In contrast, 4a combined both effects within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds.

Author keywords:

Index keywords:

1,4 dihydropyridine derivative; 2 cyano 1 (1,1 dimethylpropyl) 3 (3 pyridyl)guanidine; calcium channel; isradipine; noradrenalin; pinacidil; potassium channel; potassium channel stimulating agent; ani

DOI:

10.1021/jm990443h

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https://www.scopus.com/inward/record.uri?eid=2-s2.0-17144453163&doi=10.1021%2fjm990443h&partnerID=40&md5=6a9507553ae2a9e00a0f15c226d56140

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Поле	Значение
Link	https://www.scopus.com/inward/record.uri?eid=2-s2.0-17144453163&doi=10.1021%2fjm990443h&partnerID=40&md5=6a9507553ae2a9e00a0f15c226d56140
Affiliations	Institute of Organic Chemistry, Natl. Academy of Sciences of Ukraine, 5 Murmanskaya Str., 253660 Kiev-94, Ukraine; Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Köln, Germany; Department of Pharmacology, University Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany
Chemicals/CAS	1,4-dihydropyridine, 3337-17-5; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Pinacidil, 85371-64-8; Potassium Channels; Vasodilator Agents
Tradenames	p 1075
References	Petko, K.I., Rechitskii, A.N., Maletina, I.I., Yagupolskii, L.M., Fluorine-containing aryl-cyanoguanidines - New drug pinacidile analogues (1996) Ukr. Khim. Zhurn., 62, pp. N11; Maletina, I.I., Petko, K.I., Shavaran, S.S., Klebanov, B.M., Lozinski, M.O., Yagupolskii, L.M., Synthesis and cardiovascular effects of fluorine-containing arylcyanoguanidines (pinacidil analogues) (1997) Khim.-Farm. Zhurn., 31, pp. N6; Szewczyk, A., Marban, E., Mitochondria: A new target for K+ channel openers? (1999) Trends Pharmacol. Sci., 20, pp. 157-161; Kastron, V.V., Duburs, G.Ya., Vitolin', R.O., Skrastin'sh, I.P., Kimenis, A.A., Synthesis and pharmacological activity of 4-(o-difluoromethoxyphenyl)-1,4-dihydropyridines (1985) Khim.-Farm. Zhurn., 19, pp. N5; Shelyazhenko, S.V., Fialkov, Yu.A., Yagupolskii, L.M., Synthesis and reactions of difluoromethoxy-and difluorochlo-romethoxy derivatives of benzene (1992) Zhurn. Org. Khim., 28, pp. N8; Meisheri, K.D., Swirtz, M.A., Purohit, S.R., Cipkus-Dubay, L.A., Khan, S.A., Oleynek, J.J., Characterization of K- channel-dependent as well as -independent components of pinacidil-induced vasodilation (1991) J. Pharmacol. Exp. Ther., 256, pp. 492-499; Bosse, E., Bottlender, R., Kleppisch, T., Hescheler, J., Welling, A., Hofmann, F., Flockerzi, V., Stable and functional expression of the calcium channel alpha1 subunit from smooth muscle in a somatic cell line (1992) EMBO J., 11, pp. 2033-2038; Bean, B.P., Nitrendipine block of cardiac calcium channels: High affinity binding to the inactivated state (1984) Proc. Natl. Acad. Sci. U.S.A., 81, pp. 6388-6392; Mulvany, M.J., Halpern, W., Contractile properties of small arterial resistance vessels in normotensive and spontaneously hypertensive rats (1977) Circ. Res., 41, pp. 19-26; Herzig, S., Jischa, J., Beinhauer, A., Geirhos, B., Tacke, K., Hempelmann, R.G., Quinidine-induced potentiation of cardiovascular effects of nitrendipine: Functional aspects and possible molecular mechanisms (1995) Naunyn-Schmiedeberg's Arch. Pharmacol., 351, pp. 636-643; Löffler-Walz, C., Quast, U., Binding of KATP channel modulators in rat cardiac membranes (1998) Br. J. Pharmacol., 123, pp. 1395-1402
Correspondence Address	Herzig, S.; Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Koln, Germany; email: stefan.herzig@uni-koeln.de
CODEN	JMCMA
PubMed ID	10602711
Language of Original Document	English
Abbreviated Source Title	J. Med. Chem.
Source	Scopus