TC-5619: An alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia

Abstract

A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the α4β2, ganglionic (α3β4) and muscle subtypes. The transgenic th(tk−)/th(tk−) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.

Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia

“…Indeed, studies have shown that drugs activating muscarinic or nicotinic acetylcholine receptor (nAChR) subtypes have potential for the treatment of cognitive symptoms in patients with schizophrenia (for review, see Jones et al, 2012). Specifically, nicotine, as well as agonists and positive allosteric modulators of a7 and a4b2 nAChRs, attenuate various cognitive deficits in rodent models of schizophrenia (Boess et al, 2007;Hashimoto et al, 2008;Hauser et al, 2009;Hurst et al, 2005;Pichat et al, 2007;Rushforth et al, 2011;Thomsen et al, 2009;Timmermann et al, 2007;Wallace et al, 2011;Wildeboer and Stevens, 2008;Wishka et al, 2006). Our observations that nicotine reverses the selective CMOR impairment in rats treated with subchronic NMDAR antagonists is consistent with studies using standard object recognition tasks and extends these findings by implicating nAChRs in the potential treatment of multisensory integration deficits in schizophrenia.…”

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

“…This focus has led to the discovery of a number of distinct ␣7 agonists, including the spirofused quinuclidines (5S)-spiro[1,3-oxazolidine-5,8Ј-1-azabicyclo-[2.2.2]octane]-2-one (AR-R17779) (Mullen et al, 2000) and AZD-0328 (Sydserff et al, 2009), quinuclidine amides including PNU-282987 (Bodnar et al, 2005) (Wishka et al, 2006), TC-5619 (Hauser et al, 2009), and the related carbamate JN-403 (Feuerbach et al, 2009), SSR180711 (Biton et al, 2007;Pichat et al, 2007) Table 3 for details of potency. Roncarati et al, 2009), octahydro-pyrrolopyrrole A-582941 (Bitner et al, 2007;Tietje et al, 2008), and other yet undisclosed molecules (Taly et al, 2009).…”

“…Several other novel ␣7 nAChR agonists-(2R)-spiro-[1-azabicyclo[2.2.2]octane-3,2(3H)-furo [2,3-b]pyridine]-tartrate (AZD-0328) (Sydserff et al, 2009), 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide (SEN-12333/WAY-317538) (Roncarati et al, 2009) (Feuerbach et al, 2009), 2[2(4-bromophenyl)-2-oxoethyl]-1-methyl-pyridinium chloride (S24795) (Lopez-Hernandez et al, 2007), and N- [2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619) (Hauser et al, 2009)-have been recently described. Although these compounds have provided considerable insight supporting the involvement of ␣7 nAChRs in cognitive and learning functions, the majority of them have inherent limitations.…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…This compound also demonstrated a sufficient PK profile, with rapid CNS permeability, and activity in exploration in the rat social recognition model and an improved mouse sensory gating profile (DBA/2). Another amide quinuclidine compound (Targacept's [Winston-Salem, NC] TC-5619) demonstrated potency and selectivity for a7 nAChRs (net Therapeutic Potential of a7 nAChRs current EC 50 = 33 nM), with full efficacy relative to ACh in Xenopus oocytes (Hauser et al, 2009). TC-5619 (a7 nAChR K i = 1 nM) exhibited superior in vitro selectivity against human 5-HT 3 receptors (IC 50 .…”