Syntheses, calcium channel antagonist and anticonvulsant activities of substituted 1,4-dihydro-3,5-pyridinedicarboxylates containing various 3-alkyl ester substituents.
A group of 3-alkyl 5-isopropyl 4-aryl-1,4-dihydro-2,6-dimethyl- 3,5-pyridinedicarboxylates 10-20 containing an amine, quaternary ammonium, aryl (heteroaryl)alkenyl, 4-(4-fluorophenyl)- piperazin-1-yl or methoxy moiety in the C-3 alkyl ester R-substituent in combination with a C-4 phenyl ring bearing a 2,3-Cl2, 3-NO2, 3-NMe2, 4-NMe2 or 3,4,5-(OMe)3 X-substituent were prepared using the Hantzsch 1,4-dihydropyridine reaction. In vitro calcium channel antagonist activity (CCA) was determined using a guinea pig ileum longitudinal smooth muscle assay. In the C-4 3-nitrophenyl series of compounds, the C-3 ester R-substituent was a determinant of CCA activity where the relative potency order was -CH2CH2CH=C-(2-methylphenyl)2 > or = -CH2CH2NMe2.HCI> -CH2CH2CH=C-(3-methyl-2-thienyl)2 > -CH2CH2+NMe3I -. The position and nature of the C-4 phenyl X-substituent, were also determinants of CCA activity where the relative activity order was 3-NMe2 > 4-NMe2 > 3,4.5-(OMe)3. Anticonvulsant activities were determined in mice using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The compounds investigated were generally not effective for protecting against scMet induced seizures, except for 10 (X = 2,3-Cl2, R = 2-[4-(4- fluorophenyl)piperazin-l-yl]ethyl] and 14a (X = 3-NMe2.HCl, R = CH2CH2OMe), which exhibited modest activity. Compound 11a (X = 3-NO2, R = -CH2CH2NMe2.HCl) was the most effective agent in the MES screen. All of the compounds investigated, except for 11b (X = 3-NO2, R = -CH2CH2+NMe3 I-, Kp = 0.15), are lipophilic with n-octanol/aqueous phosphate buffer (pH = 7.4) partition coefficients (Kp) in the 121-424 range relative to the reference drug nimodipine (Kp = 187). The structure-activity relationships acquired reinforce the concept that calcium is only one of several factors that are involved in seizure generation.
Yiu
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Knaus
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D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D003998:Dicarboxylic Acids; D011725:Pyridines; D011976:Receptors, Muscarinic