Muscarinic M1 receptor agonists: can they improve cognitive performance?

Due to their potential roles in the pathophysiologies of a number of central nervous system disorders such as depression (Dilsaver, 1986), schizophrenia (Raedler et al. 2006), Alzheimer’s disease (Araujo et al. 1988) and Parkinson’s disease (Ruberg et al. 1982), modulation of the muscarinic system has been a focus of drug discovery for decades. Particular attention has been paid to developing ligands for the muscarinic M1 receptor because of the role it is thought to play in cognition (Anagnostaras et al. 2003) and the molecular processes associated with it (Giessel & Sabatini, 2010). Given the potential markets for a cognitive enhancer, especially in Alzheimer’s disease and schizophrenia, where not only are cognitive impairments key features (Coyle et al. 1983; Nuechterlein et al. 2004) but M1 function also appears to be compromised (Dean et al. 2002; Harrison et al. 1991; Mancama et al. 2003; Overk et al. 2010; Scarr et al. 2009; Shiozaki et al. 2001; Zavitsanou et al. 2004), it is not surprising that the M1 receptor has been the focus of significant drug development. However, the orthosteric binding site of the muscarinic receptors has been highly conserved during evolution (Langmead et al. 2008), hindering the design of subtype selective ligands and resulting in unacceptable side-effect profiles due to the off-target activation of peripheral, predominantly M2 and M3, muscarinic receptors (Bymaster et al. 2003).