In vitro and in vivo profile of PT-31 GIRSUPAN, a novel α2-adrenoceptor agonist with analgesic properties

Abstract

Abstract The compound 3-(2-chloro-6-fluoro-benzyl)-imidazolidine-2,4-dione (PT-31 GIRSUPAN; PT-31) has analgesic effects through the activation of a2-adrenoceptors in the central nervous system. Furthermore, when administered via the intraperitoneal (IP) route in mice (15 mg/kg), the compound shows a synergistic effect with morphine. This study aimed to investigate some properties of PT-31, namely partition coefficient (logP) and chemical stability in vitro (buffer) and ex vivo (rat plasma), and to evaluate its pharmacokinetic profile in Wistar rats after IP and oral administration as a single dose. PT-31 was also administered alone and combined with morphine in Wistar rats to assess liver and kidney toxicity and the potential for addiction. An HPLC-MS/MS bioanalytical method was developed and validated to determine PT-31, which showed suitable confidence limits for the intended application. The log P of PT-31 was 1.2 using the shake flask method. In the pharmacokinetic study of the compound administered alone, the clearance (Cl) observed was similar between IP and oral routes, but the distribution volume (0.978 and 0.681 L/kg, respectively) and elimination half-life (3.7 and 2.9 h, respectively) were significantly higher in oral administration (p<0.05). The compound has high oral absorption compared to that IP administration. PT-31 when combined with morphine showed changes in pharmacokinetic parameters. No changes in biochemical parameters related to liver and kidney function were observed. The results of locomotor activity demonstrated that the compound did not change the behavior of the animals at the doses administered (3, 5, 10, and 20 mg/kg), indicating that the compound had no addictive potential. These findings showed that the PT-31 GIRSUPAN has promising features for potential clinical application.