ABSTRACT
Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzopyrans/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Pain/drug therapy , Pyrimidines/therapeutic use , Spiro Compounds/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Arthritis/chemically induced , Arthritis/drug therapy , Arthritis/physiopathology , Benzopyrans/administration & dosage , Benzopyrans/chemical synthesis , Capsaicin , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/chemical synthesis , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , Ketoprofen/administration & dosage , Ketoprofen/pharmacology , Mice , Nociception/drug effects , Pain/chemically induced , Pain/physiopathology , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Spiro Compounds/administration & dosage , Spiro Compounds/chemical synthesisABSTRACT
Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC50 of 0.68 (0.32-1.4) µM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α2-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.