Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as alfa-4-beta-2 nicotinic acetylcholine receptor ligands

Heugebaert, Thomas; Van Overtveldt, Melissa; De Blieck, Ann; Wuyts, Benjamin; Augustijns, Patrick; Ponce-Gamez, Eugenia; Rivera, Alicia; De Groote, Dominic; Lefebvre, Romain; Wouters, Patrick; Meert, Theo; Devulder, Jacques; Stevens, Christian

doi:10.1039/c3ra44379e

Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as alfa-4-beta-2 nicotinic acetylcholine receptor ligands

Author:

Heugebaert, Thomas

Van Overtveldt, Melissa ; De Blieck, Ann ; Wuyts, Benjamin ; Augustijns, Patrick ; Ponce-Gamez, Eugenia ; Rivera, Alicia ; De Groote, Dominic ; Lefebvre, Romain ; Wouters, Patrick ; Meert, Theo ; Devulder, Jacques ; Stevens, Christian

Keywords:

Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, THERAPEUTIC TARGETS, CHOLINERGIC SYSTEM, AGONIST, EXPRESSION, PAIN, METABOLISM, DISEASE, MODELS, 03 Chemical Sciences, 34 Chemical sciences

Abstract:

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 α 4 β 2 subtype of the nicotinic acetylcholine receptor. Their K 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. © 2014 The Royal Society of Chemistry.