Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α₄β₂ nicotinic acetylcholine receptor ligands

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 a 4 b 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.

Beyond the Diketopiperazine Family with Alternatively Bridged Brevianamide F Analogues

“…A subset of compounds was tested against different targets that were chosen on the basis of the interest of the laboratory for those targets and on the basis of biological activities displayed by natural product analogous to these compounds.…”

Epibatidine: A Promising Natural Alkaloid in Health

“…Studies on epibatidine metabolism and metabolites excretion have undergone gradual decreased in number due to its severe side effects. More recently, efforts have been made to address the pharmacokinetics of new derivatives of epibatidine with reduced toxicity, as reported by Heugebaert et al [18]. The authors presented five epibatidine analogs containing a substituent on the azabicyclo[2.2.1]heptane bridgehead, namely a ketone linker, an OH linker, an aminomethyl linker, and two ethyl linkers containing an OH and a NH 2 group, respectively.…”

“…Only ketone-binding epibatidine maintained chlorine in the aromatic ring. However, the authors focused their attention only on an aminomethyl- and two ethyl linkers containing an OH and a NH 2 group, due to their higher affinity for α4β2 nAChR [18], and for them studied the in vitro pharmacokinetics. Both compounds showed a low binding affinity to plasma proteins, meaning that they are available for metabolism [18].…”

“…However, the authors focused their attention only on an aminomethyl- and two ethyl linkers containing an OH and a NH 2 group, due to their higher affinity for α4β2 nAChR [18], and for them studied the in vitro pharmacokinetics. Both compounds showed a low binding affinity to plasma proteins, meaning that they are available for metabolism [18]. Using isolated rat hepatocytes, an evaluation of metabolic stability was carried out and the results indicated compounds with an OH linker as metabolically stable, while the metabolism of an aminomethyl linker seemed to be concentration-dependent and faster than that of control (verapamil), thus hampering its t 1/2 (<2 min, compared to t 1/2 = 175 min for OH binding compound; the half-time (t 1/2 ) is a pharmacokinetic parameter, being defined as the required time to decrease half of the concentration of an active substance in plasma) [18].…”