Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Abstract

Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

“…The present findings support and extend evidence that M 4 mAChRs are the likely target involved in the APD-like activity reported with the M 1 /M 4 -preferring muscarinic agonist xanomeline (see Jones et al, 2012). M 4 mAChRs are expressed in multiple cortical and limbic regions thought to be disrupted in neuropsychiatric disorder like schizophrenia, where they function as both pre-and postsynaptic Rats were injected (arrow) after collecting 30-min baseline data.…”

“…Development of allosteric ligands provides a novel approach to address these issues (see Jones et al, 2012). Our group and others have identified subtype-selective mAChR ligands that activate a specific receptor subtype at sites that are less highly conserved than the orthosteric binding site of acetylcholine (ACh) and more topographically distinct, termed allosteric sites.…”

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).…”

Neurotherapeutics

“…Moghaddam and Javitt (2012) present the history of the glutamate hypothesis of schizophrenia, a critical evaluation of the hypothesis and avenues for future drug development. Jones et al (2012) reviews the great progress on the development of sub-type selective muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of positive and negative symptoms, including cognitive disturbances, of schizophrenia. Vinogradov et al (2012) present the history of cognitive training applications and then focus on an innovative systems neuroscience approach for cognitive training that has been applied to patients with schizophrenia.…”