Cihat Şafak

Synthesis and evaluation of 1,4-dihydropyridine derivatives with calcium channel blocking activity.

Abstract1,4-Dihydropyridines (DHPs) are an important class of L-type calcium channel blockers that are used to treat conditions such as hypertension and angina. Their primary target in the cardiovascular system is the Cav1.2 L-type calcium channel isoform, however, a number of DHPs also block low-voltage-activated T-type calcium channels. Here, we describe the synthesis of a series of novel DHP derivatives that have a condensed 1,4-DHP ring system (hexahydroquinoline) and report on their abilities to block both L- and T-type calcium channels. Within this series of compounds, modification of a key ester moiety not only regulates the blocking affinity for both L- and T-type channels, but also allows for the development of DHPs with 30-fold selectivity for T-type channels over the L-type. Our data suggest that a condensed dihydropyridine-based scaffold may serve as a pharmacophore for a new class of T-type selective inhibitors.

Vasorelaxing properties of some phenylacridine type potassium channel openers in isolated rabbit thoracic arteries.

In this study, 12 new 2,2,7,7-tetramethyl-9-aryl-2,3,4,5,6,7,9,10-octahydro-1,8-acridindione derivatives were synthesised and their effects on vascular potassium channels and mechanism of induced relaxations on phenylephrine-induced contractile responses in isolated rabbit thoracic arteries was investigated. Pinacidil was used as standard potassium channel openers in this study. Compounds 1-12 and pinacidil exerted concentration-dependent relaxation responses precontracted phenylephrine in the aortic rings with the efficacy order: 11>pinacidil>7>2>8>3>1>4>10>6>9>5>12.

Synthesis and calcium antagonistic activity of 2,6,6-trimethyl-3-carbomethoxy(ethoxy)-4-aryl-1,4,5,6,7,8-hexahydroquinoline derivatives

Twelve new 2,6,6-trimethyl-3-carbomethoxy(ethoxy)-4-aryl-1,4.5,6.7,8-hexahydroquinoline derivatives have been prepared. Their structures were confirmed by IR, 1H NMR, mass and elemental analysis. The calcium antagonistic activity of these compounds was tested in rat aortic rings precontracted with 30 mM K+. The compounds IVa, IVc, IVe, IVf, IVh-l induced concentration dependent relaxation response in precontracted aortic rings. The concentrations that cause 50% relaxation of K+-contraction were also calculated for the compounds IVe, IVf, IVj. According to pharmacological results, compound IVl exert the most activity and compound IVc has been found to be least active in this series. The methyl ester derivatives carrying mono halogensubstitutent in the phenyl ring, the activity order is F > Br > Cl. Replacement of the substituted phenyl ring with the pyridine ring increases the activity.

Analgesic effect of a broad-spectrum dihydropyridine inhibitor of voltage-gated calcium channels

Voltage-activated calcium channels are important facilitators of nociceptive transmission in the primary afferent pathway. Consequently, molecules that block these channels are of potential use as pain therapeutics. Our group has recently reported on the identification of a novel class of dihydropyridines (DHPs) that included compounds with preferential selectivity for T-type over L-type channels. Among those compounds, M4 was found to be an equipotent inhibitor of both Cav1.2 L- and Cav3.2 T-type calcium channels. Here, we have further characterized the effects of this compound on other types of calcium channels and examined its analgesic effect when delivered either spinally (i.t.) or systemically (i.p.) to mice. Both delivery routes resulted in antinociception in a model of acute pain. Furthermore, M4 was able to reverse mechanical hyperalgesia produced by nerve injury when delivered intrathecally. M4 retained partial activity when delivered to Cav3.2 null mice, indicating that this compound acts on multiple targets. Additional whole-cell patch clamp experiments in transfected tsA-201 cells revealed that M4 also effectively blocks Cav3.3 (T-type) and Cav2.2 (N-type) currents. Altogether, our data indicate that broad-spectrum inhibition of multiple calcium channel subtypes can lead to potent analgesia in rodents.

Condensed 1,4-dihydropyridines with various esters and their calcium channel antagonist activities

New alkyl 2,6,6-(2,7,7)-trimethyl-4-(2-fluoro-3-chloro-5-trifluoromethylphenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and 9-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-6,6(7,7)-dimethyl-6,7-dihydrofuro[3,4-b]quinoline-1,8-diones have been synthesised and their calcium antagonistic activities on isolated rabbit sigmoid colon have been investigated and compared with Nifedipine. The investigation examined the influence of ester groups in the 3-position of the HHQ ring and the 2-methoxyethyl analogs were found to be the most active derivatives.

Substituted 9-aryl-1,8-acridinedione derivatives and their effects on potassium channels

In this study, 12 new 3,6-dimethyl-9-aryl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-diones derivatives were synthesized. Synthesis of the compounds was realized by the reaction of 5-methyl-1,3-cyclohexanedione, the appropriate aromatic aldehyde, and ammonium acetate in methanol. The structure of the compounds was elucidated by infrared (IR), 1H-nuclear magnetic resonance (NMR), 13C-NMR, mass spectroscopy, and elemental analysis. Functional effects of the compounds on vascular potassium channels and mechanism of phenylephrine-induced contractile responses were investigated in isolated rat aorta rings. Pinacidil was used as a standard potassium channel opener.

Synthesis and Myorelaxant Activity of Fused 1,4‐Dihydropyridines on Isolated Rabbit Gastric Fundus

Strategy, Management and Health Policy Preclinical Research

9-(5-Bromo-1H-indol-3-yl)-1,2,3,4,5,6,7,8,9,10-deca­hydro­acridine-1,8-dione dimethyl sulfoxide monosolvate

In the title compound, C21H19BrN2O2·C2H6OS, the indole ring system is essentially planar, with a maximum deviation of 0.050 (3) Å for the non-bridgehead C atom adjacent to the N atom. The two cyclohex-2-enone rings adopt half-chair conformations. An intramolecular C—H⋯O hydrogen bond occurs. The solvent molecule exhibits minor disorder of the S atom [site occupancies = 0.8153 (16) and 0.1847 (18)]. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming layers parallel to the bc plane.

Microwave-assisted synthesis and myorelaxant activity of 9-indolyl- 1,8-acridinedione derivatives

In this study a microwave-assisted method was applied for the synthesis of novel 9-(substituted indolyl)-3,4,6,7-tetrahydroacridine-1,8-(2H,5H,9H,10H)-dione derivatives. The structures of the compounds were confirmed by spectral methods including X-ray studies and elemental analysis. The Emax and pD2 values of the compounds and pinacidil were determined on noradrenaline precontracted tissues of isolated strips of rabbit gastric fundus smooth muscle. The obtained results indicated that some compounds and pinacidil produced concentration-dependent relaxation on the strips. The efficacy of compound 9 was higher than pinacidil. Docking studies were carried out to understand the interactions of the compounds with the active site of potassium channel. Methyl substituents on the acridine backbone and bromine atom on the indole ring led to more active compounds.

Investigation of myorelaxant activity of 9-aryl-3,4,6,7-tetrahydroacridine-1,8-(2H,5H,9H,10H)-diones in isolated rabbit gastric fundus

In this study, twelve compounds having 9-aryl-3,4,6,7-tetrahydroacridine-1,8-(2H,5H,9H,10H)-dione structure were synthesized by reaction of 5-methyl-1,3-cyclohexanedione, the appropriate aromatic aldehydes, and ammonium acetate in methanol. The structures of the compounds were elucidated by infrared, 1H- and 13C-nuclear magnetic resonance spectroscopy (-NMR), mass spectroscopy, and elemental analysis. The maximum relaxant effects (Emax) and pD2 values of the compounds 3a–l and pinacidil were tested on isolated strips of rabbit gastric fundus smooth muscle.