MONOSUBSTITUTED-3,8-DIAZABICYCLO[3.2.1]OCTANE AND DISUBSTITUTED-3,8-DIAZABICYCLO[3.2.1]OCTANE DERIVATIVES AS ANALGESICS STRUCTURALLY RELATED TO EPIBATIDINE - SYNTHESIS, ACTIVITY, AND MODELING

A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or at the 8 position (compounds 2) by a chlori nated heteroaryl ring were synthesized, as potential analogues of the potent natural analgesic epibatidine. When tested in the hot plate ass ay, the majority of the compounds showed significant effects, the most interesting being the hloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]oct ane (1a). At a subcutaneous dose of 1 mg/kg, 1a induced a significant increase in the pain threshold, its action lasting for about 45 min. 1 a also demonstrated good protection at a dose of 5 mg/kg in the mouse abdominal constriction test, while at 20 mg/kg it completely prevented the constrictions in the animals, Administration of naloxone (1 mg/kg ip) did not antagonize its antinociception while mecamylamine (2 mg/k g ip) did, thus suggesting the involvement of the nicotinic systemin i ts action, Binding studies confirmed high affinity for the alpha(4) be ta(2) nAChR subtype (K-i = 4.1 +/- 0.21 nM). nAChR functional activity studies on three different cell lines showed that 1a was devoid of an y activity at the neuromuscular junction. Finally, due to the analogy in their pharmacological profile with that of epibatidine, compounds w ere compared from a structural and conformational point of view throug h theoretical calculations and high-field H-1 NMR, spectroscopy. Resul ts indicate that all of them present one conformation similar to that of epibatidine.