Download PDF
Arzneimittelforschung 2008; 58(12): 659-665
DOI: 10.1055/s-0031-1296568
Antiemetics · Gastrointestinal Drugs · Uricosuric Drugs · Urologic Drugs
Editio Cantor Verlag Aulendorf (Germany)

Synthesis of 2-Methyl-4-aryl-4,6,7,8-tetrahydro-5(1H)-quinolone Derivatives and their Effects on Potassium Channels

Gökçe Sevim Öztürk
1   Department of Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
,
Mert Vural
1   Department of Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
,
Miyase Gözde Gündüz
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
,
Rahime Şimşek
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
,
Yusuf Sanoğlu
1   Department of Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
,
Cihat Şafak
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2011 (online)

    Permissions and Reprints

Abstract

In this study, twelve compounds having 2-methyl-4-aryl-4,6,7,8-tetrahydro-5(1H)-quinolone structure have been synthesized by the reaction of 4-aryl-3-butene-2-on derivatives with 1,3-cyclohexanedione analogs in the presence of ammonium acetate in methanol. The structures of the compounds have been elucidated by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elementel analysis. Their potassium channel opener activities have been investigated on isolated rabbit bladder smooth muscle using pinacidil (CAS 85371-64-8) as standard. The test compounds and pinacidil caused concentration-dependent relaxation responses in bladder smooth muscle strips precontracted with 80 mmol/L KCl with the efficacy order: pinacidil ≥ 3g ≥ 3j ≥ 3a ≥ 3l ≥ 3i ≥ 3c=3b ≥ 3d ≥ 3h ≥ 3k. In bladder smooth muscle strips precontracted with 15 mmol/L KCl, the efficacy order was: pinacidil > 3h ≥ 3c≥ 3j ≥3g ≥3l ≥ 3i=3b ≥ 3k ≥ 3f ≥ 3a. The test compounds and pinacidil caused concentration-dependent inhibition of electrical field stimulation-evoked contractile responses in the bladder smooth muscle strips with the efficacy order: 3j ≥ 3l ≥ pinacidil ≥ 3k ≥ 3h ≥ 3a ≥ 3g ≥ 3c ≥ 3i ≥ 3b ≥ 3f.

Key words

Potassium channel openers - Quinolones, effects on potassium channels, synthesis
 

  • Literature

  • 1 Doyle DA, Morais CJ, Pfuetzner RA, Kuo A, Gulbis JB, Cohen L et al. The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity. Science. 1988; 280: 69-77
    PubMedGoogle Scholar
  • 2 Foray M, Lancelin J, Hollecker M, Marion D. Sequence-Specific 1H-NMR Assignment and Secondary Structure of Black Mamba Dendrotoxin I, A Highly Selective Blocker of Voltage-Gated Potassium Channels. Eur J Biochem. 1993; 211 (V) 813-820
    CrossrefPubMedGoogle Scholar
  • 3 Lu Z, MacKinnon R. Purification, Characterization, and Synthesis of Inward-Rectifier K+ Channel Inhibitör from Scorpian Venom. Biochemistry. 1997; 36: 6936-6940
    CrossrefPubMedGoogle Scholar
  • 4 Simsek R, Ozkan M, Kismetli E, Uma S, Safak C. Some Arylacridine Derivatives Possessing Potassium Channel Opening Activity. Farmaco. 2004; 59: 939-943
    CrossrefPubMedGoogle Scholar
  • 5 Berkan O, Saraç B, Simşek R, Yildirim S, Sarioğlu Y, Safak C. Vasorelaxing Properties of Some Phenylacridine Type Potassium Channel Openers in Isolated Rabbit Thoracic Arteries. Eur J Med Chem. 2002; 37 (6) 519-523
    CrossrefPubMedGoogle Scholar
  • 6 Carroll WA, Altenbach RJ, Bai H, Brioni JD, Brune ME, Buckner SA et al. Synthesis and Structure-activity Relationships of a Novel Series of 2,3,5,6,7,9-hexahidrothieno [3,2-b]quinolin-8(4H)-one-1,1-dioxide K(ATP) Channel Openers: Discovery of (–)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahidrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), A Potent K(ATP)opener That Selectively Inhibits Spontaneous Bladder Contractions, J Med Chem. 2004; 47 (12) 3163-3179
    CrossrefPubMed
  • 7 Shieh CC, Feng J, Buckner SA, Brioni JD, Coghlan MJ, Sullivan JP et al. Functional Implication of Spare ATP-sensitive K+ Channels in Bladder Smooth Muscle Cells. J Pharmacol Exp Ther. 2001; 296 (3) 669-75
    PubMedGoogle Scholar
  • 8 Davis-Taber R, Molinari EJ, Altenbach RJ, Whiteaker KL, Shieh CC, Rotert G et al. A Novel High-affinity 1,4-dihidropyridine ATP-sensitive K+ Channel Opener: Characterization and Pharmacology of Binding. Mol Pharmacol. 2003; 64 (1) 143-153
    CrossrefPubMedGoogle Scholar
  • 9 Ohnmacht JR, Cyrus J, Trainor D, Forst JM, Stein MM, Haris RJ. 4,6,7,8-Tetrahidro-5(1H)-quinolones Useful for the Treatment of Urinary Incontinence. US. Pat. 1995; 5.455-253
    PubMedGoogle Scholar
  • 10 Grant Tl, Zuzack JS. Effects of Potassium Channel Blockers and Cromakalim (BRL 34915) on the mechanical Activity of Guinea Pig Detrusor Smooth Muscle. Pharmacol Exp Ther. 1991; 259 (3) 1158-1164
    PubMedGoogle Scholar
  • 11 Erol K, Ulak G, Dönmez T, Cingi MI, Alpan RS, Özdemir M. Effects of Vasoactive Intestinal Polypeptide on Isolated Rat Urinary Gladder Smooth Muscle. Urol Int. 1992; 49: 151-153
    CrossrefPubMedGoogle Scholar
  • 12 Drizin I, Holladay MW, Yi L, Zhang HQ, Gopalakrishnan S, Gopalakrishnan M et al. Structure-Activity Studies for a Novel Series of Tricyclic Dihidropyrimidines as K(ATP) Channel Openers (KCOs). Bioorg Med Chem Lett. 2002; 12 (11) 1481-1484
    CrossrefPubMedGoogle Scholar
  • 13 Nicoll RA, Malenka RC, Kauer JA. Functional Comparison of Neurotransmitter Receptor Subtypes in Mammalian Central Nervous System. Physiol Rev. 1990; 70 (2) 513-65
    PubMedGoogle Scholar
  • 14 Roeper J, Pongs O. Presynaptic Potassium Channels. Curr Opin Neurobiol. 1996; 6 (3) 338-341
    CrossrefPubMedGoogle Scholar
  • 15 Mathie A, Wooltorton JR, Watkins CS. Voltage-activated Potassium Channels in Mammalian Neurons and Their Block by Novel Pharmacological Agents. Gen Pharmacol. 1998; 30 (1) 13-24
    CrossrefPubMedGoogle Scholar
  • 16 Nakamura K, Okada S, Yamaguchi N, Shimizu T, Yokotani K, Yokotani K. Role of K+channels in M2 Muscarinic Receptor-mediated Inhibition of Noradrenaline Release From the Rat Stomach. J Pharmacol Sci. 2004; 96 (3) 286-292
    CrossrefPubMedGoogle Scholar
  • 17 Sanguinetti MC, Spector PS. Potassium Channelopathies. Neuropharmacology. 1997; 36 (6) 755-762
    CrossrefPubMedGoogle Scholar
  • 18 Noma E. ATP-regulated K+ Channels in Cardiac Muscle. Nature. 1983; 305: 147-148
    CrossrefPubMedGoogle Scholar
  • 19 Lange U, Loffler-Walz C, Englert HC, Hambroc A, Russ U, Quast U. The Stereoenantiomers of Apinasidil Analog Open or Close Cloned ATP-sensitive K+ Channels. J Biol Chem. 2002; 25: 40196-40205
    PubMedGoogle Scholar
  • 20 Loussouarn G, Pike LJ, Ashcroft FM, Makhina EN, Nichols CG. Dynamic Sensitivity of ATP-sensitive K+ Channels to ATP. J Biol Chem. 2001; 276: 29098-29103
    CrossrefPubMedGoogle Scholar
  • 21 Aronson JK. Potassium Channels in Nervous Tissue. Biochem Pharmacol. 1992; 43 (1) 11-14
    CrossrefPubMedGoogle Scholar
  • 22 Frank CA, Forst JM, Grant T, Harris RJ, Kau ST, Li HJ et al. Dihidropyridine KATP Potassium Channel Openers. Bioorg Med Chem Lett. 1993; 3 (12) 2725-2726
    CrossrefPubMedGoogle Scholar
  • 23 Nurse DA, Restorick JM, Mundy AR. The Effect of Cromakalim on the Normal and Hyperreflexic Human Detrusor Muscle. Br J Urol. 1991; 68: 27-31
    CrossrefPubMedGoogle Scholar
  • 24 Loev B, Goodman MM, Snader MK, Tedeschi R, Macko E. Hantzsch-type Dihidropyridine Hypotensive Agents. J Med Chem. 1974; 317 (9) 956-965
    PubMedGoogle Scholar
  • 25 Klöckner U, Trieschmann U, Isenberg G. Pharmacological Modulation of Calcium and Potassium Channels in Isolated Vascular Smooth Muscle Cells. Arzneimittel-Forschung (Drug Research). 1989; 39 (1) 120-126
    PubMedGoogle Scholar
  • 26 Ashcroft SJ, Ashcroft FM. Properties and Functions of ATP-sensitive K-channels. Cell Signal. 1990; 2 (3) 197-214
    CrossrefPubMedGoogle Scholar
  • 27 Ashcroft FM, Gribble FM. New Windows on the Mechanism of Action of K(ATP) Channel Openers, Trends Pharmacol Sci. 2000; 21 (11) 439-445
    PubMed
  • 28 Ashcroft FM, Rorsman P. Electrophysiology of the Pancreatic β-cell. Prog Biophys Mol Biol. 1989; 54 (2) 87-143
    CrossrefPubMedGoogle Scholar
  • 29 MacKinnon R, Yellen G. Mutations affecting TEA Blockade and Ion Permeation in Voltage-activated K+ Channels. Science. 1990; 12: 276-279
    PubMedGoogle Scholar
  • 30 Reinhart PH, Chung S, Levitan IB. A Family of Calcium-dependent Potassium Channels from Rat Brain. Neuron. 1989; 2 (1) 1031-1041
    CrossrefPubMedGoogle Scholar
  • 31 Blatz AL, Magleby KL. Single Apamin-blocked Ca-activated K+ Channels of Small Conductance in Cultured Rat Skeletal Muscle. Nature. 1986; 323: 718-720
    CrossrefPubMedGoogle Scholar
  • 32 Tagaya E, Tamaoki J, Takemura H, Nagai A. Regulation of Adrenergic Nerve-mediated Contraction of Canine Pulmonary Artery by K+ Channels. Eur Respir J. 1998; 11 (3) 571-574
    PubMedGoogle Scholar
  • 33 Cook NS. The Pharmacology of Potassium Channels and Their Therapeutic Potential. Trends Pharmacol Sci. 1988; 9 (1) 21-28
    CrossrefPubMedGoogle Scholar
  • 34 Miyoshi Y, Nakaya Y. Angiotensin II Blocks ATP-Sensitive K+ Channels in Porcine Coronary Artery Smooth Muscle Cells. Biochem Biophys Res Commun. 1991; 181 (2) 700-706
    CrossrefPubMedGoogle Scholar
  • 35 Zhang H, Bolton TB. Activation by Intracellular GDP, Metabolic Inhibition and Pinasidil of a Glibenclamide-sensitive K-channel in Smooth Muscle Cells of Rat Mesenteric Artery. Br J Pharmacol. 1995; 114 (3) 662-672
    CrossrefPubMedGoogle Scholar
  • 36 Teramoto N, Brading AF. Activation by Levcromakalim and Metabolic Inhibition of glibenclamide-sensitive K Channels in Smooth Muscle Cells of Pig Proximal Urethra. Br J Pharmacol. 1996; 118 (3) 635-642
    CrossrefPubMedGoogle Scholar
  • 37 Lee SW, Wang HZ, Christ GJ. Characterization of ATP-sensitive Potassium Channels in Human Corporal Smooth Muscle Cells. Int J Impot Res. 1999; 11 (4) 179-188
    CrossrefPubMedGoogle Scholar
  • 38 Andersson KE. Advances in the Pharmacological Control of the Bladder. Exp Physiol. 1999; 4 (1) 95-213
    PubMedGoogle Scholar