Małgorzata Zygmunt1, Marietta Ślusarczyk2, Agnieszka Jankowska2, Artur Świerczek3, Adrian Bryła1, Szczepan Mogilski1, Grzegorz Kazek1, Jacek Sapa1, Elżbieta Wyska3, Grażyna Chłoń-Rzepa4. 1. Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna str., 30-688, Kraków, Poland. 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna str., 30-688, Kraków, Poland. 3. Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna str., 30-688, Kraków, Poland. 4. Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna str., 30-688, Kraków, Poland. grazyna.chlon-rzepa@uj.edu.pl.
Abstract
BACKGROUND: To verify the validity of the proposed pain treatment approach, which is based on concomitant blocking of the Transient Receptor Potential Ankyrin 1 (TRPA1) channel and phosphodiesterases (PDEs) 4B/7A activity, we continued our pharmacological studies on 8-alkoxypurine-2,6-diones selected based on previous in vitro screening. METHODS: Derivatives 17, 31, and 36 were pharmacologically evaluated in vivo using the formalin test and oxaliplatin-induced neuropathic pain: the von Frey and the cold plate tests, and in the carrageenan-induced edema model. Compound 36, which turned out to be the most promising, was further evaluated in the collagen-induced arthritis model. The pharmacokinetic parameters of this compound were also estimated. RESULTS: All the tested compounds exhibited significant analgesic and anti-inflammatory activities. Compound 36 was additionally characterized by an antiarthritic effect and showed a favorable pharmacokinetic profile in rats. CONCLUSION: The compounds evaluated in this study represent a new class of derivatives with analgesic and anti-inflammatory activities that involve TRPA1 antagonism and PDE4/7 inhibition.
BACKGROUND: To verify the validity of the proposed pain treatment approach, which is based on concomitant blocking of the Transient Receptor Potential Ankyrin 1 (TRPA1) channel and phosphodiesterases (PDEs) 4B/7A activity, we continued our pharmacological studies on 8-alkoxypurine-2,6-diones selected based on previous in vitro screening. METHODS: Derivatives 17, 31, and 36 were pharmacologically evaluated in vivo using the formalin test and oxaliplatin-induced neuropathic pain: the von Frey and the cold plate tests, and in the carrageenan-induced edema model. Compound 36, which turned out to be the most promising, was further evaluated in the collagen-induced arthritis model. The pharmacokinetic parameters of this compound were also estimated. RESULTS: All the tested compounds exhibited significant analgesic and anti-inflammatory activities. Compound 36 was additionally characterized by an antiarthritic effect and showed a favorable pharmacokinetic profile in rats. CONCLUSION: The compounds evaluated in this study represent a new class of derivatives with analgesic and anti-inflammatory activities that involve TRPA1 antagonism and PDE4/7 inhibition.
Authors: Miriam Redondo; José Brea; Daniel I Perez; Ignacio Soteras; Cristina Val; Concepción Perez; Jose A Morales-García; Sandra Alonso-Gil; Nuria Paul-Fernandez; Rocío Martin-Alvarez; María Isabel Cadavid; María Isabel Loza; Ana Perez-Castillo; Guadalupe Mengod; Nuria E Campillo; Ana Martinez; Carmen Gil Journal: J Med Chem Date: 2012-03-16 Impact factor: 7.446
Authors: Fiona E McCann; Andrew C Palfreeman; Melanie Andrews; Dany P Perocheau; Julia J Inglis; Peter Schafer; Marc Feldmann; Richard O Williams; Fionula M Brennan Journal: Arthritis Res Ther Date: 2010-06-02 Impact factor: 5.156
Authors: Artur Świerczek; Krzysztof Pociecha; Marietta Ślusarczyk; Grażyna Chłoń-Rzepa; Sebastian Baś; Jacek Mlynarski; Krzysztof Więckowski; Monika Zadrożna; Barbara Nowak; Elżbieta Wyska Journal: Pharm Res Date: 2020-01-02 Impact factor: 4.200