Opioidergic and GABAergic mechanisms underlie the anti-nociceptive effects of adamantane amino thiazole derivatives: synthesis, toxicity evaluation and mechanistic insights using standard pre-clinical models.

The present study involves the synthesis, toxicity assessment and investigation of anti-nociceptive potential of two adamantane amino thiazole derivatives (AATD), including [N-((1s, 3s)-adamantan-1-yl)-4-(4-bromophenyl)thiazol-2-amine] (AATD1) and [2-(2-(((1s, 3s)-adamantan-1-yl)amino)thiazol-4-yl)-5-bromophenol] (AATD2). These derivatives were obtained through a multistep synthesis by reacting amantadine with benzoyl chloride. The amantadine substituted thiourea obtained on subsequent hydrolysis was cyclized with alpha bromo acetophenone. In this regard we aimed to synthesize novel compounds utilizing adamantane and thiazole rings, both being medicinally valuable moieties, in the hope of obtaining safe and potent analgesic agents. In acute toxicity study, the synthesized compounds were administered to the BALB/c mice (up to 800 mg/kg dose). No signs of any toxicity or mortality were observed at the tested doses. The sub-acute toxicity screening involved the intraperitoneal administration of 15, 30 mg/kg doses of compounds to BALB/c mice for 28 days followed by isolation of liver and kidneys for histopathological evaluation. Moreover, blood specimens were collected for determining biochemical parameters including LFTs and RFTs. The test compounds were further evaluated for their potential anti-nociceptive properties at 15 mg/kg and 30 mg/kg doses using phasic thermal nociceptive paradigms including tail immersion, hotplate tests and chemically induced tonic visceral nociceptive test like acetic acid induced writhing assay. The histological screening demonstrated no significant alterations, except mild sinusoidal dilatation, lymphocyte infiltration and inflammatory changes in the liver tissues. Slight tubular dilatations in the kidneys were observed at 30 mg/kg doses. Biochemical investigations correlated with the histological findings, indicating no significant elevation in the ALP, AST, ALT, BUN and serum creatinine. The synthesized compounds demonstrated considerable anti-nociceptive effects indicated by an increase in the latency time in tail immersion, hotplate tests. A decline in the number of writings was observed in acetic acid induced writhing test. The anti-nociceptive effect of compounds was impeded by opioid receptor antagonist, naloxone (1 mg/kg), and GABA receptor antagonist, pentylenetetrazole (15 mg/kg) which suggest the possible involvement of opioid and GABA receptors. Our findings suggest that our synthesized compounds are considerably safe and exhibit promising analgesic effects possibly mediated via opioidergic and GABAergic anti-nociceptive mechanisms.