Abstract
The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1–10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1–10 mg/kg, sc) and set shift performance in rats (1–10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1–3 mg/kg, po). BMS-933043 also improved auditory gating (0.56–3 mg/kg, sc) and mismatch negativity (0.03–3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.
Highlights
Schizophrenia is a severe disorder affecting 0.5–1% of the population and resulting in poor social and occupational functioning
These receptors are highly expressed in the cortex and hippocampus and activation results in i) increased presynaptic release of gamma aminobutyric acid (GABA), glutamate, dopamine, acetylcholine and 5-hydroxytryptamine (5-HT), ii) increased postsynaptic cell excitability through direct membrane depolarization and iii) activation of intracellular, calciumdependent, biochemical signaling cascades that are critical for synaptic strength, plasticity and the formation of long term memory [8,9,10]
These findings have subsequently been extended with several novel α7 nAChR agonists reported to improve cognition in rodents treated with N-methyl-D-aspartate (NMDA) receptor antagonists to mimic schizophrenia-like deficits including RG3487 (N[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride), SSR-180711
Summary
Schizophrenia is a severe disorder affecting 0.5–1% of the population and resulting in poor social and occupational functioning. Homomeric α7 nAChRs are notable for their high permeability to Ca2+, rapid desensitization, low affinity for nicotine and high affinity for the antagonist, methyllycaconitine (MLA) [7] These receptors are highly expressed in the cortex and hippocampus and activation results in i) increased presynaptic release of gamma aminobutyric acid (GABA), glutamate, dopamine, acetylcholine and 5-hydroxytryptamine (5-HT), ii) increased postsynaptic cell excitability through direct membrane depolarization and iii) activation of intracellular, calciumdependent, biochemical signaling cascades that are critical for synaptic strength, plasticity and the formation of long term memory [8,9,10]. While tropisetron is a potent 5-HT3 receptor antagonist used clinically for the treatment of postoperative and chemotherapy induced nausea and emesis, this agent alleviates cognitive deficits in phencyclidine (PCP) treated mice, an effect which was blocked by MLA consistent with α7 nAChR involvement [17]. These findings have subsequently been extended with several novel α7 nAChR agonists reported to improve cognition in rodents treated with N-methyl-D-aspartate (NMDA) receptor antagonists to mimic schizophrenia-like deficits including RG3487 (N[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride), SSR-180711
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