Epibatidine Analogs Synthesized for Characterization of Nicotinic Pharmacophores—A Review

Abstract

In 1992 Daly and co-workers reported the isolation of a new natural product, epibatidine. Future studies showed that epibatidine was an nAChR ligand with analgesic potency 200–400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine’s unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the α4β2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction.

Acid‐Catalyzed Intramolecular Imination / Nucleophilic Trapping of 4‐Aminobutanal Derivatives: One‐Pot Access to 2‐(Pyrazolyl)pyrrolidines

“…Pyrrolidine ring is an important structural part of many natural alkaloids and one of the most frequently occurring heterocyclic scaffolds in approved drugs In recent years, the number of 2‐diazole substituted pyrrolidine derivatives patented as drugs increased sharply, indicating growing interest in the practical application of such compounds. Examples are antiviral drugs Velpatasvir and Daclatasvir used in the treatment of hepatitis C infection, anti‐cancer drugs Acalabrutinib (approved by FDA in 2017) (Figure ).…”

Nicotinic Acetylcholine Receptor Accessory Subunits Determine the Activity Profile of Epibatidine Derivatives

“…Epibatidine has been an important inspiration to nicotinic drug development and a valuable tool for the characterization of nicotinic receptor binding sites (Carroll, 2009;Houghtling et al, 1995). Like epibatidine, the three analogs used in the present study show high affinity for heteromeric nAChR and very low affinity for -type receptors, (Table 2).…”

“…It is an efficacious activator of some nAChR subtypes (Table 1). It has been shown to be an extremely potent analgetic agent (Badio and Daly, 1994), and it has been used extensively as a scaffold to generate numerous novel and probative receptor ligands (Carroll, 2009). In this paper, we report the activity profile of three such derivatives Figure 1on eight different nAChR subtypes, in all but one case controlling the precise receptor subunit composition through the use of linked subunit concatamers (Kuryatov and Lindstrom, 2011;Zhou et al, 2003) (Figure 2).…”

Design, synthesis, and biological activity of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors

“…These molecular descriptors were calculated for compounds 1 , 2 3a – 3e , as well as reference compounds nicotine and epibatidine (Table 1). In general, successful drugs used for treating CNS disorders have a clog P in the range 2–4[29], TPSA less than 76 Å[30] and logBB greater than −1[31]. All the compounds have clogP values (2.08 – 4.04) within the range of CNS drugs, and run higher than the reference compounds nicotine and epibatidine.…”