Epibatidine, a novel nicotinic receptor agonist

Abstract

It is speculated that nicotine receptor ligands might be of therapeutic benefit for the treatment of obesity, anxiety, and memory loss. With the exception of nicotine, few selective high-affinity agents exist. (-)Epibatidine (1), isolated from Ecuadoran frogs, shows structural resemblence to (-)nicotine (2). Molecular modeling studies reveal that the N to N distance in 1 (5.5 Å) is greater than that found in 2 (4.9 Å). This distance exceeds that previously considered optimal for the nicotine receptor pharmacophore (4.8. ± 0.3 Å) by about half a bond length. Nevertheless 1 binds (Ki = 0.055 nM) at [³H]nicotine-labeled receptors with higher affinity than 2 (Ki = 1.5 nM). Although our studies are still in progress, molecular superimposition and preliminary results with various structurally modified analogs suggest that it is the conformationally constraíned nature of 1 that accounts for its high affinity. For example, 6-chloronicotine binds only with slightly higher affinity (Ki = 0.6 nM) than nicotine suggesting, at least for nicotine, that the chloro substituent is tolerated but does not contribute significantly to binding. Excision of the ethano bridge of deschloroepibatidine, to yield isonornicotine (Ki = 12.5 nM), results in reduced affinity. Isonicotine binds with similar (Ki = 7.3 nM) affinity. The bridged azabicycloheptane system likely fixes the structure of epibatidine in a highly receptor-preferred conformation. The pharmacophore for nicotine receptor binding will require reconsideration and should take into account the longer N-N distance of epibatidine. The N-N distance in epibatidine may be optimal, whereas that in isonornicotine is longer, and that for nicotine shorter. (Supported in part by funding from TDC/CIT.)