Epibatidine is a natural alkaloid that acts at nicotinic acetylcholine receptors (nAChRs). The present review aims to carefully discuss the affinity of epibatidine and its synthetic derivatives, analogues to nAChRs for α4β2 subtype, pharmacokinetic parameters, and its role in health. Published literature shows a low affinity and lack of binding of epibatidine and its synthetic analogues to plasma proteins, indicating their availability for metabolism. Because of its high toxicity, the therapeutic use of epibatidine is hampered. However, new synthetic analogs endowed from this molecule have been developed, with a better therapeutic window and improved selectivity. All these aspects are also discussed here. On the other hand, many reports are devoted to structure⁻activity relationships to obtain optically active epibatidine and its analogues, and to access its pharmacological effects. Although pharmacological results are obtained from experimental studies and only a few clinical trials, new perspectives are open for the discovery of new drug therapies.

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Epibatidine: A Promising Natural Alkaloid in Health

Synthesis of saturated nitrogen heterocycles by Strecker reaction – nucleophilic cyclization

A method for the preparation of 3,5-bridged piperazin-2-ones from a tryptophan-proline-based diketopiperazine is described using diphosgene to induce the ring closure. Density functional theory calculations were conducted to study the mechanism of this C-C bond formation. Several derivatives of the thus obtained α-chloroamine were synthesized by substitution of the chlorine atom using a range of O-, N-, S-, and C-nucleophiles. This novel class of brevianamide F analogues possess interesting breast cancer resistance protein inhibitory activity.

Beyond the Diketopiperazine Family with Alternatively Bridged Brevianamide F Analogues.

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 α4β2 subtype of the nicotinic acetylcholine receptor. Their Ki 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.

http://www.chtf.stuba.sk/~szolcsanyi/education/files/Chemia%20heterocyklickych%20zlucenin/Prednaska%204/Doplnkove%20studijne%20materialy/Epibatidine/Synthesis%20of%201-substituted%20epibatidine%20analogues.pdf

Eugenia Ponce-Gámez

Papers

Synthesis of 1-substituted epibatidine analogues and their in vitro and in vivo evaluation as α4β2nicotinic acetylcholine receptor ligands