Effects of 4-(2-Alkylthio-1-benzyl-5-imidazolyl)-Dihydropyridines on the Isolated Rat Colon and Right Atrium Contractility

Document Type: Original Article

Authors

1 Department of Medicinal Chemistry, School of Pharmacy and Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Atlantic Centre for Comparative Biomedical Research, Charlottetown, PEI, Canada. (Former Faculty member of Department of Physiology and Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran)

Abstract

Objectives
In order to provide a pharmacological profile for some newly synthesized dihydropyridines, we investigated their effects on the isolated rat colon segments and the isolated rat atrium contractility. The tested compounds include alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-alkylthio-1-benzyl-5-imidazolyl substituent, and nifedipine as a positive control substance.
Materials and Methods
Isolated rat colon and atrial tissues were prepared. Rat colon was contracted with 80 mM KCl, and maximum response was recorded (100%).  After washing tissue with Krebs solution it was preincubated with different concentrations of test compounds and again KCl was added and percent change in contraction was calculated. Spontaneous contractions and its frequency for colon and atrium before and after addition of test compounds were also recorded and percent change was calculated. Nifedipine (10-8 -10-5 M) was used as positive control at all experiments.
Results
The compounds showed similar effects to that of nifedipine on the isolated rat colon. The potency of these analogues with concentration range 10-5 to 10-4 M was compared to potency of nifedipine which was effective at 10-8 to 10-5 M (P<0.01). However, unlike nifedipine, the test compounds exerted significant positive inotropic effect on the isolated rat atrium (P < 0.01). Our observations suggest that these analogues of nifedipine selectively enhance contractility of heart muscle while causing relaxation of intestinal smooth muscle.
Conclusion
These compounds may serve as valuable probes to develop novel dihydropyridines with dual smooth muscle relaxant effect and positive inotropic action.

Keywords


1. Fleckenstien A. Pecific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle. Ann Rev Pharmacol Toxicol1977; 17:149.

2. Ramesh M, Matowe WC, Wolowyk MW, Knaus EE. Synthesis and calcium channel antagonist activity of alkyl t-butyl esters of nifedipine analogues containing pyridinyl substituents. Drug Des Deliv1987; 2:79-89.

3. Akula MR, Matowe WC, Wolowyk MW, Knaus EE. Synthesis and calcium channel antagonist activity of alkyl cycloalkyl esters of nifedipine containing pyridinyl substituents. Drug Des Deliv1989; 5:117-123.

4. Ramesh M, Matowe WC, Knaus EE, Wolowyk MW. Synthesis and calcium channel antagonist activity of dialkyl 1, 4-dihydro-2, 6-dimethyl-4-[3-(1-methoxy-carbonyl-4-substituted-1,4- dihydro-pyridyl)]-3,5-pyridinedicarboxylates. Drug Des Discov1992; 8:313-323.

5. Akula MR, Matowe WC, Wolowyk MW, Knaus EE. Synthesis and calcium channel antagonist activity of 3-arylmethyl 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates. Pharm Res1990; 7:919-922.

6. Vo D, Matowe WC, Ramesh M, Iqbal N, Wolowyk MW, Howlett SE, et al. Syntheses, calcium channel agonist-antagonist modulation activities, and voltage-clamp studies of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate racemates and enantiomers. J Med Chem1995; 38:2851-2859.

7. Mahmoudian M, Mirkhani H, Nehardani Z, Ghiaee S. Synthesis and biological activity of two new calcium-channel blockers, mebudipine and dibudipine. J Pharm Pharmacol 1997; 49:1229-1233.

8. Shafiee A, Dehpour AR, Hadizadeh F, Azimi M. Syntheses and calcium channel antagonist activity of nifedipine analogue with methylsulfonylimidazolyl substituent. Pharma ActaHelv1998; 73:75-79.

9. Triggle DG. Biochemical and pharmacological differences among calcium channel antagonists: clinical implications. In: Epstein M, ed. Calcium Antagonists in Clinical Medicine. Philadelphia, PA: Hanley & Belfus, Inc.; 1992:1-27.

10.  Iqbal N, Vo D, McEwen CA, Wolowyk MW, Knaus EE. Enantioselective syntheses and calcium channel modulating effects of (+)- and (-)-3-isopropyl 5-(4-methylphenethyl)1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylates. Chirality1994;6:515-520.

11.  Baraldi P, Garuti L, Leonin A. Synthesis and cardiodepressant activity of dialkyl1,4-dihydro-2,6-dimethyl-4-(pentatomic-heteroaryl)-3,5-pyridinedicarboxylates. DrugDesDiscov 1993; 10:319.

12.  Shafiee A, Miri R, Dehpour AR. Synthesis and calcium cannel antagonist-activity of nifedipine analogues containing nitroimidazolyl substituents. Pharm Sci 1996; 2:541.

13.  Amini A, Dehpour AR, Shafiee A. Synthesis and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing dichloromidazolyl substituents. Arzneim Forsch / Drug Res2002; 52:21.

14.  Shafiee A, Rastkary N, Jorjani M.Synthesis and calcium channel antagonist-activity of 1,4- dihyropyridine derivatives containing 4-nitro imidazolyl substituents. Arzneim Forsch / Drug Res 2002; 52:537.

15.  Pourmorad F, Hadizadeh F, Shafiee A. Synthesis and calcium channel antagonist activity of 4- imidazolyl-1,4-dihydropyridines. Pharm Sci1997; 3:165.

16.  Zarghi A, Derakhshandeh K, Roshanzamir F. Synthesis and calcium channel antagonist activity of new 1, 4-dihyropyridines containing nitrobenzyl imidazolyl substituent. Boll Chim Farm2002; 141:15.

17.  Hadizadeh F, Shafiee A, Kazemi R, Mohammadi M. Synthesis of 4-(1-phenylmethyl-5-imidazolyl)-1,4-dihydropyridines as calcium channel antagonists. Indian J Chem Sec B 2002; 41:2679.

18.  Miri R, Javidnia K, Sarkarzadeh H, Hemmateenejad B. Synthesis, study of 3D structures, and pharmacological activities of lipophilic nitroimidazolyl-1,4-dihydropyridines as calcium channel antagonist. Bioorg Med Chem 2006; 14:4842-4849.

19.  Nasa Y, Ichihara K, Yshida R, Abiko Y. Positive inotropic and negative chronotropic effects of (-)-cis-diltiazem in rat isolated atria. Br J Pharmacol 1992; 105: 696-702.

20.  Gurkan A, Birgul Y, Ziya K. Direct cardiac effects in isolated perfused rat hearts of fentanyl and remifentanil. Ann Card Anaesth 2005; 8: 140-144.

21.  Christensen J, Stiles MJ, Rick GA, Sutherland J. Comparative anatomy of the myenteric plexus of the distal colon in eight mammals. Gastroenterology1984; 86:706-713.

22.  Ek BA, Bjellin LA, Lundgren BT. Beta-adrenergic control of contraction in the rat colon. I. Evidence for functional separation of the beta 1- and beta 2-adrenoceptor-mediated inhibition of colon activity. Gastroenterology1986; 90:400-407.

23.  Serio R, Mule F, Postorino A. Nonadrenergic, noncholinergic inhibitory junction potentials in rat proximal colon: role of nitric oxide. Can J Physiol Pharmacol1995; 73:79-84.

24.  Hjalmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol1998; 21:II3-7.

25.  Hockerman GH, Peterson BZ, Johnson BD, Catterall WA. Molecular determinants of drug binding and action on L-type calcium channels. Ann Rev Pharmacol Toxicol 1997; 37:361-396.

26.          Zhang Z, Xu Y, Song H, Rodriguez J, Tuteja D, and Namkung Y, et al. Functional roles of Ca (v) 1.3 (alpha (1D) calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice. Circ Res 2002; 90:981-987.