We disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-α), nitric oxide and cannabinoid receptor subtype 1 (CB₁). We report herein the synthesis and neuropharmacological screening results of the titled compounds in two acute pain and two neuropathic pain models in rodents. Particularly the analogue N-(4-bromophenyl)-3-tert-butyl-5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide (8a) exhibited pronounced acute antinociceptive efficacy, also being effective in chronic constriction injury (ED₅₀ = 23.8 mg/kg) and partial sciatic nerve injury (ED₅₀ = 29.0 mg/kg) models with CB₁ receptor activity (IC₅₀ = 49.6 nM) and inhibitory effect on TNF-α (86.4% inhibition at 100 mg/kg). These results suggest the importance of the development of this lead as multi-targeted treatment strategy for neuropathic pain.
Keywords: Antiallodynic; Antihyperalgesic; Antioxidant; Cannabinoid receptor; Nitric oxide; Tetrahydropyrazolo-pyridine.
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