A-366833: A novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane α4β2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models

Abstract

5-[(1 R,5 S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([ 3H]-cytisine) with K i value of 3.1 nM and exhibits agonist selectivity at α4β2 nAChR relative to the α3β4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 μmol/kg (i.p.). In addition, A-366833 demonstrated significant effects in acute thermal pain (6.2–19.0 μmol/kg, i.p.), formalin (1.9–19 μmol/kg i.p.) and SNL (1.9–19 μmol/kg i.p.) models. The systemic effects of A-366833 were attenuated by pretreatment with mecamylamine (5 μmol/kg i.p.) in both the formalin and SNL models, suggesting that the analgesic effects of A-366833 in models of persistent nociceptive and neuropathic pain are mediated by activation of nAChRs. Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5 h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at α4β2 vs. α3β4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects.