title: Synthesis, antinociceptive activity and pharmacokinetic profiles of nicorandil and its isomers.
abstract: Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate) is an antianginal drug, which activates guanylyl cyclase and opens the ATP-dependent K(+) channels, actions that have been suggested to mediate its vasodilator activity. We synthesized nicorandil and its two isomers, which vary in the positions of the side chain containing the nitric oxide (NO) donor, and also their corresponding denitrated metabolites. The activities of these compounds were evaluated in an experimental model of pain in mice. Pharmacokinetic parameters of nicorandil and its isomers, as well as the plasma concentrations of the corresponding denitrated metabolites and also nicotinamide and nitrite were determined. Nicorandil exhibited the highest antinociceptive activity, while the ortho-isomer was the least active. Nicorandil and para-nicorandil, which induced higher plasma concentrations of nitrite, exhibited higher antinociceptive activity, which suggests that the release of NO may mediate this activity.
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Isabela C
authors.initials: IC
authors.lastname: César
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Godin
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Débora P
authors.initials: DP
authors.lastname: Araujo
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Francinely C
authors.initials: FC
authors.lastname: Oliveira
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Raquel R
authors.initials: RR
authors.lastname: Menezes
authors.affiliation: Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Julliana R A
authors.initials: JR
authors.lastname: Santos
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Mariana O
authors.initials: MO
authors.lastname: Almeida
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Marcela M G B
authors.initials: MM
authors.lastname: Dutra
authors.affiliation: Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Santos
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Renes R
authors.initials: RR
authors.lastname: Machado
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Gerson A
authors.initials: GA
authors.lastname: Pianetti
authors.affiliation: Department of Pharmaceutical Products, School of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Márcio M
authors.initials: MM
authors.lastname: Coelho
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil. Electronic address: adefatima@qui.ufmg.br.
authors.forename: Angelo
authors.initials: A
authors.lastname: de Fátima
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006207:Half-Life; D007536:Isomerism; D051379:Mice; D020108:Nicorandil / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy
chemical_list: D000700:Analgesics; D020108:Nicorandil
keywords: Antinociceptive activity; NO-releasing drugs; Nicorandil; Nicotinamide; Nitric oxide; Nitrite