Syntheses, calcium channel agonist-antagonist modulation activities, and nitric oxide release studies of nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate racemates, enantiomers, and diastereomers.

Abstract

A novel group of hybrid calcium channel (CC) modulators was prepared where the isopropyl ester moiety of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate (PN 202-791) was replaced by a variety of nitric oxide (*NO) donor nitrooxyalkyl ester substituents. Enantiomers, or diastereomers, having the (R)-configuration at the C-4 position of the 1,4-dihydropyridine ring (1,4-DHP) exhibited more potent in vitro CC antagonist activity on guinea pig ileum longitudinal smooth muscle (GPILSM) than compounds having the (4S)-configuration. None of the nitrooxyalkyl compounds exhibited a contraindicated CC agonist effect on GPILSM that would cause smooth muscle contraction. Structure-activity studies showed the enantiomers having the (S)-configuration at the C-4 position of the 1,4-DHP ring or diastereomers having the a (4S)-configuration at the C-4 position of the 1,4-DHP ring in conjunction with a (1R-)-1-methyl-2-nitrooxyethyl ester substituent exhibited the most potent cardiac CC agonist (positive inotropic) activity on guinea pig left atrium (GPLA). This class of compounds releases *NO in vitro that is enhanced by the presence of a thiol such as N-acetylcysteamine. The novel *NO donor (-)-(S,R)-1-methyl-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate [(-)-(S,R)-38], which acts as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calciumchannel antagonist (GPILSM), is a useful lead compound for drug discovery targeted to the treatment of congestive heart failure, and it provides a useful research probe to study the structure-function relationship of calcium channels.

• Authors: Rudong Shan, Carlos Velazquez, Edward E Knaus
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 1 Pg. 254-61 (Jan 01 2004) ISSN: 0022-2623 [Print] United States
• PMID: 14695839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-methyl-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate
• Calcium Channel Blockers
• Calcium Channels
• Nitrates
• Nitric Oxide Donors
• Oxadiazoles
• Nitric Oxide

Topics

• Animals
• Calcium Channel Blockers (chemical synthesis, chemistry, pharmacology)
• Calcium Channels (drug effects)
• Guinea Pigs
• Heart (drug effects, physiology)
• Ileum (drug effects, physiology)
• In Vitro Techniques
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects, metabolism, physiology)
• Myocardium (metabolism)
• Nitrates (chemical synthesis, chemistry, pharmacology)
• Nitric Oxide (chemistry)
• Nitric Oxide Donors (chemical synthesis, chemistry, pharmacology)
• Oxadiazoles (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Stimulation, Chemical
• Structure-Activity Relationship