title: Analgesic, antiallodynic, and anticonvulsant activity of novel hybrid molecules derived from N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide and 2-(2,5-dioxopyrrolidin-1-yl)butanamide in animal models of pain and epilepsy.
abstract: The purpose of the present study was to examine the analgesic activity of six novel hybrid molecules, which demonstrated in the previous research anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure (scPTZ) tests in mice. The antinociceptive properties were estimated in three models of pain in mice-the hot plate test, the formalin test, and in the oxaliplatin-induced neuropathy. Moreover, extended anticonvulsant studies were carried out and the antiseizure activity was investigated in the 6-Hz test. Considering drug safety evaluation, the influence of compounds on locomotor activity and contextual memory were checked. Furthermore, chosen molecules were tested in vitro for potential hepatotoxicity. To explain the probable mechanism of action, the radioligand binding assays were performed. In both phases of formalin test, analgesic activity demonstrated compounds 4, 8, and 9. These agents relieved also mechanical allodynia in oxaliplatin-induced model of neuropathic pain. At active doses, they did not influence locomotor activity of mice. Moreover, for compounds 8 and 9, no deleterious effect on memory was observed, but compound 4 might induce memory deficits. All tested compounds (4, 5, 8, 9, 15, and 16) inhibited psychomotor seizures with the ED50values = 24.66-47.21 mg/kg. The binding studies showed that compound 4 only at the high concentrations revealed the effective binding to the neuronal sodium channels and moderately binding to the L-type calcium (verapamil site) channels and NMDA receptors. The present preclinical results proved that novel hybrid molecules demonstrate very promising anticonvulsant and analgesic activity.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. a.rapacz@uj.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Koczurkiewicz
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy / Q000473:pathology; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement; D010433:Pentylenetetrazole / Q000008:administration & dosage; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000700:Analgesics; D000927:Anticonvulsants; D010433:Pentylenetetrazole
keywords: Binding studies; Formalin; Hot plate; Hybrid compounds; Oxaliplatin; Psychomotor seizures