Synthesis and photodegradation studies of analogues of muscle relaxant 1,4-dihydropyridine compounds.

This paper describes the synthesis of 1,4-dihydropyridine compounds (DHPs) endowed with good muscle relaxant activity and stability to light. Six new condensed DHPs were synthesized by the microwave irradiation method. A long-chain ester moiety [2-(methacryloyloxy)ethyl] and various substituents on the phenyl ring were demonstrated to affect the muscle relaxant activity occurring in isolated rabbit gastric fundus smooth muscle strips. Forced photodegradation conditions were applied to the molecules according to the ICH rules. The degradation profile of the drugs was monitored by spectrophotometry coupled with the multivariate curve resolution technique. Formation of the oxidized pyridine derivative was observed for all the studied DHPs, except for one compound, which showed very fast degradation and formation of a second photo-product. Pharmacological tests on the molecules showed a good muscle relaxing effect, with a mechanism similar to that of nifedipine, however, proving to be more stable to light.

Photodegradation studies of 1,4-dihydropyridine compounds by MCR analysis on UV spectral data.

BACKGROUND: 1,4-Dihydropyridines (DHPs) are well-known light-sensitive compounds. Photostability studies are necessary to ensure safety in therapy. MATERIALS & METHODS: Photodegradation experiments on 15 condensed DHP derivatives were made according to the International Conference on Harmonization rules. Degradation profiles were monitored by spectrophotometry and the data were processed by multivariate curve resolution analysis. RESULTS: The analysis of the spectral data showed the formation of a single photoproduct from two DHPs, due to the aromatization of the pyridine ring. Traces of a second photoproduct were revealed in 12 DHPs and a third photoproduct was verified only in one case. CONCLUSION: DHPs showed high stability when fluorine was in the position R1 of the phenyl ring or simultaneously present in R1 and R2 positions. In contrast, the presence of chlorine in R1 or R2 strongly increased the degradation.

Synthesis and Biological Evaluation of New Tricyclic Dihydropyridine Based Derivatives on Potassium Channels.

The present study reports a microwave-assisted method for the synthesis of twelve novel tricyclic 1,4-dihydropyridine derivatives in which dimethyl-substituted cyclohexane and / or tetrahydrothiophene rings are fused to the DHP ring. The structures of the compounds were confirmed by spectral methods and elemental analysis. The potassium channel opening effects of the compounds were determined on rat mesenteric arteries and urinary bladders. The obtained results indicated that some compounds produced mesenteric artery-selective relaxant properties and the effects of these compounds were mediated through ATP-sensitive potassium channels. The replacement of the second tetrahydrothiophene ring with dimethyl-substituted cyclohexane ring led to more active compounds. Docking studies were carried out to understand the interactions of the compounds with the active site of potassium channel. The unsubstituted nitrogen atom on the 1,4-dihydropyridine ring and one of the sulfonyl oxygens were found to be important for the formation of hydrogen bonds to stabilize the compound in the center of the cavity. The nature and position of phenyl ring substituents were also effective on the activity of the compounds. Finally, a theoretical study was established to predict the ADME of the most active compounds.

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.

1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain.

We have recently identified a class of dihydropyridine (DHP) analogues with 30-fold selectivity for T-type over L-type calcium channels that could be attributed to a modification of a key ester moiety. Based on these results, we examined a second series of compounds with similar attributes to determine if they had enhanced affinity for T-type channels. Whole-cell patch clamp experiments in transfected tsA-201 cells were used to screen these DHP derivatives for high affinity and selectivity for Cav3.2 over Cav1.2 L-type channels. The effects of the two lead compounds, termed N10 and N12, on Cav3.2 channel activity and gating were characterized in detail. When delivered intrathecally or intraperitoneally, these compounds mediated analgesia in a mouse model of acute inflammatory pain. The best compound from the initial screening, N12, was also able to reverse mechanical hyperalgesia produced by nerve injury. The compounds were ineffective in Cav3.2 null mice. Altogether, our data reveal a novel class of T-type channel blocking DHPs for potential pain therapies.

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.

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

1,4-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.

Ethyl 2,7,7-trimethyl-4-(1-methyl-1H-indol-3-yl)-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate.

In the title mol-ecule, C24H28N2O3, the cyclo-hexene ring is in a sofa conformation and the 1,4-dihydro-pyridine ring is in a slight boat conformation. In the indole ring system, the pyrrole and benzene rings form a dihedral angle of 2.63 (7)°. In the crystal, N-H⋯O hydrogen bonds connect the mol-ecules into C(6) chains parallel to the b axis and pairs of weak C-H⋯O hydrogen bonds link inversion-related chains into a ladder motif through R2(2)(18) rings. A weak intra-molecular C-H⋯O hydrogen bond is also observed.

2,2,7,7-Tetra-methyl-1,2,3,4,5,6,7,8-octa-hydro-acridine-1,8-dione.

The whole molecule of the title compound, C17H21NO2, is generated by twofold rotational symmetry. The N atom and the C and H atoms in position 4 of the pyridine ring lie on the twofold axis. The cyclohexene ring has a sofa conformation with the CH2 C atom adjacent to the dimethyl-substituted C atom displaced by 0.5949 (16) Šfrom the mean plane of the other five C atoms. In the crystal, weak C-H⋯O inter-actions link the mol-ecules into chains parallel to the a axis. In addition, π-π stacking inter-actions [centroid-centroid distance = 3.8444 (7) Å] contribute to the stabilization of the crystal structure.

9-(5-Bromo-1H-indol-3-yl)-1,2,3,4,5,6,7,8,9,10-deca-hydro-acridine-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) Šfor the non-bridgehead C atom adjacent to the N atom. The two cyclo-hex-2-enone rings adopt half-chair conformations. An intra-molecular C-H⋯O hydrogen bond occurs. The solvent mol-ecule exhibits minor disorder of the S atom [site occupancies = 0.8153 (16) and 0.1847 (18)]. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds, forming layers parallel to the bc plane.

3,3,6,6-Tetra-methyl-9-(1-methyl-1H-indol-2-yl)-1,2,3,4,5,6,7,8,9,10-deca-hydro-acridine-1,8-dione.

In the acridine system of the title mol-ecule, C26H30N2O2, both cyclo-hex-2-enone rings adopt sofa conformations. The indole ring system is essentially planar, with a maximum deviation of 0.017 (2) Šfor a bridgehead C atom. An intra-molecular C-H⋯O hydrogen bond occurs. The mol-ecules assemble into C(6) chains in the crystal by way of N-H⋯O hydrogen bonds.

Ethyl 4-(5-bromo-1H-indol-3-yl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate.

The title compound, C23H25BrN2O3, crystallizes with two independent mol-ecules in the asymmetric unit (Z' = 2) which differ in the twist of the 5-bromo-1H-indole ring with respect to the plane of the 4-methyl-1,4,5,6,7,8-hexa-hydro-quinoline ring [dihedral angles of 78.55 (9) and 89.70 (8)° in molecules A and B, respectively]. The indole ring is planar in both molecules [maximum deviations = 0.021 (3) and -0.020 (3) Šfor the N atom] while the cyclo-hexene ring has adopts a sofa conformation. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming dimers with R1(2)(6) ring motifs. These dimers are connected by N-H⋯O hydrogen bonds, generating chains along [110]. A C-H⋯O contact occurs between the independent mol-ecules.

Two 1,4-dihydropyridine derivatives with potential calcium-channel antagonist activity.

The title compounds, benzyl 4-(3-chloro-2-fluorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate, C(23)H(19)ClFNO(3), (I), and 3-pyridylmethyl 4-[2-fluoro-3-(trifluoromethyl)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C(26)H(24)F(4)N(2)O(3), (II), belong to a class of 1,4-dihydropyridines whose members sometimes display calcium modulatory properties. The 1,4-dihydropyridine ring in each structure has a shallower than usual shallow-boat conformation and is nearly planar in (I). In each structure, the halogen-substituted benzene ring is oriented such that the halogen substituents are in a synperiplanar orientation with respect to the 1,4-dihydropyridine ring plane. The oxocyclopentene ring in (I) is planar, while the oxocyclohexene ring in (II) has a half-chair conformation, which is less commonly observed than the envelope conformation usually found in related compounds. In (I), the frequently observed intermolecular N-H···O hydrogen bond between the amine group and the carbonyl O atom of the oxocyclopentene ring of a neighbouring molecule links the molecules into extended chains; there are no other significant intermolecular interactions. By contrast, the amine group in (II) forms an N-H···N hydrogen bond with the pyridine ring N atom of a neighbouring molecule. Additional C-H···O interactions complete a two-dimensional hydrogen-bonded network. The halogen-substituted benzene ring has a weak intramolecular π-π interaction with the pyridine ring. A stronger π-π interaction occurs between the 1,4-dihydropyridine rings of centrosymmetrically related molecules.

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.

Synthesis of 2-methyl-4-aryl-4,6,7,8-tetrahydro-5(1H)-quinolone derivatives and their effects on potassium channels.

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 > or = 3g > or = 3j > or = 3a > or = 3l = 3i > or = 3c = 3b > or = 3d > or = 3h > or = 3k. In bladder smooth muscle strips precontracted with 15 mmol/L KCl, the efficacy order was: pinacidil > 3h > or = 3c > or = 3j > or = 3g > or = 3l > or = 3i = 3b > or = 3k > or = 3f > or = 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 > or = 3l pinacidil > or = 3k > or = 3h > or = 3a > or = 3g > or = 3c > or = 3i > or = 3b > or = 3f.

Evaluation of myorelaxant activity of 7-substituted hexahydroquinoline derivatives in isolated rabbit gastric fundus.

In this article, 16 new methyl(ethyl) 4-(dichlorophenyl)-2,7-dimethyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxylates and methyl(ethyl) 2-methyl-4-(dichlorophenyl)-5-oxo-7-phenyl-l,4,5,6,7,8-hexahydroquinoline-3-carboxylate derivatives have been synthesized by the Hantzsch reaction and screened for their myorelaxant and potassium channel opening activities. The maximum relaxant effects (E(max)) and pD(2) values on exogenous noradrenaline precontracted tissues and inhibitory effects on cholinergic neurotransmission of the compounds and pinacidil were determined on isolated strips of rabbit gastric fundus smooth muscle. Obtained results indicated that some compounds and pinacidil produced concentration-dependent relaxation on rabbit gastric fundus smooth muscle strips in the two test conditions.

Synthesis and calcium modulatory activity of 3-alkyloxy-carbonyl-4-(disubstituted)aryl-5-oxo-1,4,5,6,7,8-hexa-hydroquinoline derivatives.

In this study, twelve hexahydroquinoline derivatives which are condensed analogs of the 1,4-DHP molecule were synthesized and evaluated for their calcium-antagonistic activity. The results indicated that all compounds and nifedipine produced concentration-dependent relaxation in rabbit gastric fundus smooth muscle strips. The relaxant effects of the compounds on the tissues were expressed as percentage of the precontraction using Ca(2+). The maximum response (E(max)) and pD(2)values (the negative logarithm of the concentration for the half-maximal response (EC(50))) were calculated. It is generally believed that introduction of a second electron-withdrawing substituent into the phenyl ring increases the mentioned activity. Methyl-2,7,7-trimethyl-4-(2-nitro-5-chlorophenyl)-5-oxo-l,4,5,6,7,8-hexahydroquinoline-3-carboxylate 2a has been found to be the most active compound in this serie.

Spectroscopic study of hexahydroquinoline derivatives--a potential group of calcium antagonists.

Spectral properties of 2, 6, 6-trimethyl-3-carbmethoxy-4-phenyl-5-oxo -1,4,5,6,7,8-hexahydroquinoline derivatives (HHQ) with different substituents in the phenyl ring (-Cl, -NO2, -CF3, -CH3, -OCH3) have been studied. Their emission and absorption spectra have been analyzed and quantum yields of emission were determined. The quantum yield of emission was found to depend on the kind, number, and position of substituents in the phenyl ring: it was the highest for the chlorine derivatives of HHQ, and the lowest for the compounds containing -NO2 group.

4-difluoro-substituted phenl-5-oxohexahydroquinoline derivatives and their effects on calcium channels.

Twenty new methyl(ethyl) 2,6,6- or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and ten new N,N-diethyl-2,6,6- or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide derivatives have been synthesised and screened for their calcium channel antagonistic activity. The compounds were synthesised by the Hantzsch reaction. Calcium antagonistic activities of the compounds were determined by the tests performed on isolated rat ileum and rat thoracic artery.

Fused 1,4-dihydropyridines as potential calcium modulatory compounds.

1,4-Dihydropyridine (1,4-DHP) derivatives nifedipine of which the prototype, are the most popular drugs having calcium antagonistic activity. Fused 1,4-dihydropyridines (DHPs) have also exhibit calcium modulatory activities. In this article, we emphasize calcium channels and fused 1,4-DHP derivatives affecting calcium channels. In addition, the basic considerations of synthesis, metabolism, structure-activity relationships and the latest developments on fused 1,4-DHP derivatives will be reviewed. This review also has extended examples of fused 1,4-DHP derivatives having cited activities synthesized by our group.