Synthesis of 1-substituted epibatidine analogues and their in vitroand in vivoevaluation as alpha sub(4) beta sub(2) nicotinic acetylcholine receptor ligands

The highly potent natural alkaloid epibatidine remains a source of inspiration in the search for new analgesic drugs. In this paper, we describe an expansion of our previously reported synthesis of epibatidine analogues, and five synthetic alkaloids characterized by a symmetric, 1-substituted 7-azabicyclo[2.2.1]heptane skeleton, were evaluated for their biological activity. Two of these are binding selectively to the alpha sub(4) beta sub(2) subtype of the nicotinic acetylcholine receptor. Their K sub(i) values were determined to be 40 and 290 nM. After a favourable evaluation of these compounds' cytotoxicity and metabolic stability, they were submitted to a rat tail flick test. The compounds did not show antinociceptive effects, which may be caused by a combination of insufficient potency and poor brain penetration.