Homoepiboxidines: further potent agonists for nicotinic receptors

Homoepiboxidine (3) and the corresponding N-methyl (4) and N-benzyl (5) derivatives were prepared from a 6β-carbomethoxynortropane (8). Affinities and functional activities at neuromuscular, central neuronal and ganglionic-type nicotinic receptors were compared to those of epibatidine 1, and epiboxidine 2. Homoepiboxidine had equivalent affinity/activity to epiboxidine at neuromuscular, neuronal α4β2, and most α3-containing ganglionic-type nicotinic receptors. The N-substituted derivatives showed reduced affinity/activity at most receptor subtypes. Replacement of the methylisoxazole moiety of 3 and 4 with a methyloxadiazole moiety provided analogues 6 and 7, which had greatly reduced affinity/activity in virtually all assays at nicotinic receptors. Marked analgetic activity in mice occurred at the following ip doses: epibatidine 10 μg/kg; epiboxidine 25 μg/kg; homoepiboxidine 100 μg/kg; N-methylhomoepiboxidine 100 μg/kg; the methyloxadiazole (6) 100 μg/kg. The time course at such ip doses was significantly longer for homoepiboxidine 3 with marked analgesia still manifest at 30 min post-injection. Epiboxidine and the homoepiboxidines were less toxic than epibatidine. Homoepiboxidine (R−H, X=CH), its N-methyl and N-benzyl derivatives, as well as two oxadiazole (R=H, CH3, X=N) analogues were prepared. In vitro binding and functional activities at several nicotinic acetylcholine receptor subtypes were evaluated as well as in vivo analgesia and toxicities.