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Allosteric Modulation of the Muscarinic M4 Receptor As an Approach to Treating Schizophrenia

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Allosteric Modulation of the Muscarinic M4 Receptor As an Approach to Treating Schizophrenia Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia W. Y. Chan*, D. L. McKinzie†, S. Bose*, S. N. Mitchell*, J. M. Witkin†, R. C. Thompson‡, A. Christopoulos§, S. Lazareno¶, N. J. M. Birdsallʈ, F. P. Bymaster†, and C. C. Felder*†** *Neuroscience Discovery Research, Lilly Research Centre, Surrey GU20 6PH, United Kingdom; †Neuroscience Division and ‡Discovery Chemistry and Research Technologies, Lilly Corporate Center, Indianapolis 46285; §Department of Pharmacology, Drug Discovery Biology Laboratory, Monash University, Melbourne, Victoria 3010, Australia; ¶MRC Technology, Mill Hill, London NW7 1AD, United Kingdom; and ʈDivision of Physical Biochemistry, Medical Research Council National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved April 17, 2008 (received for review January 23, 2008) Current antipsychotics provide symptomatic relief for patients types, in the pathophysiology of schizophrenia (5, 6). Muscarinic suffering from schizophrenia and related psychoses; however, receptors are genetically linked to schizophrenia and cognitive their effectiveness is variable and many patients discontinue treat- deficits (7, 8). Pharmacologically, relatively non-selective mus- ment due to side effects. Although the etiology of schizophrenia is carinic antagonists exacerbate, whereas agonists ameliorate, still unclear, a leading hypothesis implicates an imbalanced dopa- cognitive deficits and psychotic behaviors in animal models and minergic system. Muscarinic acetylcholine (ACh) receptors regulate in patients suffering from Alzheimer’s disease and schizophrenia dopamine levels in key areas of the brain involved in psychosis, (9–12). In particular, the M1/M4 preferring partial agonist, with the M4 subtype emerging as a key regulator of dopaminergic xanomeline, was found to be efficacious in animal models hyperactivity. Unfortunately, no selective small molecule tools predictive of antipsychotic behaviors through modulation of exist to provide pharmacological validation of this hypothesis. both dopamine and glutamate transmission (13). In exploratory Here, we describe the discovery of a small molecule modulator, clinical trials, xanomeline reduced psychotic behaviors and improved cognitive measures in Alzheimer’s patients (9), and LY2033298, that is highly selective for human M4 receptors by virtue of targeting an allosteric site on this receptor. Pharmaco- significantly improved positive, negative, and cognitive symp- toms in a small schizophrenia trial (12). Unfortunately, lack of logical assays confirmed the selectivity of LY2033298 for the M 4 receptor subtype selectivity led to undesirable side-effects (gas- receptor and revealed the highest degree of positive allosteric trointestinal disturbances, blood pressure dysregulation) that enhancement of ACh potency thus far identified. Radioligand rendered xanomeline as an unsuitable candidate for further binding assays also show this compound to directly potentiate clinical development (14). agonist binding while having minimal effects on antagonist bind- M receptors are most highly expressed in brain regions rich 432 4 ing. Mutational analysis identified a key amino acid (D )inthe in dopamine and dopamine receptors (15, 16). Experiments with third extracellular loop of the human M receptor to be critical for 4 muscarinic knock out mice have implicated the M4 receptor selectivity and agonist potentiation by LY2033298. Importantly, subtype in regulating dopaminergic neurons involved in move- LY2033298 was active in animal models predictive of clinical ment control and cognition (17, 18); therefore, we reasoned that antipsychotic drug efficacy indicating its potential use as a first- a highly selective M4 muscarinic receptor activator may represent in-class, selective, allosteric muscarinic antipsychotic agent. a useful candidate for the development of muscarinic-based antipsychotic agents. Unfortunately, attempts at discovering cholinergic ͉ GPCR ͉ cooperativity selective small molecule ligands for the five muscarinic receptor subtypes have largely been unsuccessful when targeted at the chizophrenia is a complex disease presenting a broad spec- receptors’ orthosteric site, i.e., the binding site for the endoge- Strum of endophenotypes that can be generalized to symp- nous agonist ACh, which is highly conserved across all five toms in three major domains: positive (hallucinations, hearing of muscarinic subtypes (19). This has been particularly true for the voices, delusions and disorganized thinking), negative (anhedo- ACh-mimetics, such as xanomeline, sabcomeline, and melame- line (20). However, it is also known that muscarinic receptors nia, flat affect), and cognitive (attention and working memory possess allosteric binding sites that have the potential to show deficits). The etiological basis for the disease is believed to derive greater sequence divergence across subtypes and, hence, may predominantly from dysregulation of dopamine and glutamate provide an alternative means of attaining receptor subtype neurotransmission pathways in mesocortical and mesolimbic selectivity (21, 22). Allosteric modulators also offer the addi- brain areas (1–3). Atypical antipsychotics are the current front- tional potential of maintaining both spatial and temporal neu- line treatment for schizophrenia, ameliorating the positive symp- rotransmission through modulation of physiologically relevant toms in approximately half of the treated patient population with receptor-mediated neural regulation, as opposed to direct (con- little efficacy at the negative and cognitive symptoms. Most atypical antipsychotics are broad spectrum G protein-coupled receptor (GPCR) antagonists, and their therapeutic action is Author contributions: W.Y.C., D.L.M., J.M.W., R.C.T., A.C., S.L., N.J.M.B., F.P.B., and C.C.F. designed research; W.Y.C., D.L.M., S.B., S.N.M., J.M.W., R.C.T., S.L., N.J.M.B., F.P.B., and mediated primarily through inhibition of dopamine D2,D3 and C.C.F. performed research; R.C.T. contributed new reagents/analytic tools; W.Y.C., S.B., D4, and serotonin 5HT2A, receptors (4). Their complex phar- S.N.M., A.C., S.L., N.J.M.B., and C.C.F. analyzed data; and W.Y.C., S.B., S.N.M., A.C., S.L., macology, however, leads to significant undesirable side effects, N.J.M.B., and C.C.F. wrote the paper. including movement disorders and weight gain. Therefore, de- Conflict of interest statement: W.Y.C., D.L.M., S.B., S.N.M., J.M.W., R.C.T., F.P.B., and C.C.F. veloping antipsychotics through an alternative mechanism may are or were employed by Eli Lilly & Co. provide better total symptom control and reduced side effects. This article is a PNAS Direct Submission. The family of five muscarinic acetylcholine (ACh) receptors Freely available online through the PNAS open access option. plays a prominent role in regulating neurotransmission in the **To whom correspondence should be addressed at: Eli Lilly & Co. Research Laboratories, CNS and may provide a mechanism for antipsychotic drug Lilly Corporate Center, Indianapolis, IN 46285. E-mail: [email protected]. discovery. Studies using muscarinic receptor knock out mice This article contains supporting information online at www.pnas.org/cgi/content/full/ have provided valuable insight into the potential role of these 0800567105/DCSupplemental. receptors, especially the muscarinic receptor M1 and M4 sub- © 2008 by The National Academy of Sciences of the USA 10978–10983 ͉ PNAS ͉ August 5, 2008 ͉ vol. 105 ͉ no. 31 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0800567105 Downloaded by guest on September 25, 2021 activation, using cell lines stably expressing the hM1–M5 recep- A tors coupled to intrinsic or engineered calcium signaling path- ways. No agonist activity at any muscarinic receptor subtype was detected when LY2033298 was applied alone. However, upon addition of a submaximal concentration of ACh, an elevated calcium response was readily detected in the hM4 cell lines relative to the effect of the same concentration of ACh in the absence of LY2033298. Subsequent assays constructed complete concentration-response curves to ACh in the presence of in- creasing concentrations of LY2033298. As shown in Fig. 1A, these experiments revealed a prototypical characteristic of pos- itive allosteric interactions: a robust potentiation of agonist potency that reached a limit at the highest concentrations of allosteric modulator above which no further effect was obtained (24). Application of an allosteric ternary complex model to the data yielded KB ϭ 200 Ϯ 40 nM for LY2033298 at the allosteric site on the unoccupied hM4 receptor, and ␣ ϭ 35 Ϯ 4 for the degree of allosteric enhancement when both orthosteric and allosteric sites are occupied; to our knowledge, this is the highest degree of positive cooperativity reported for any allosteric modulator of a muscarinic receptor. In addition, these experi- ments also revealed the high selectivity of LY2033298 for the hM4 receptor, because there was no effect at hM1/3/5 receptors at B any concentration of modulator and a very small allosteric potentiation at the closest homolog, hM2 (KB ϭ 1.0 Ϯ 0.3 ␮M; ␣ ϭ 3.7 Ϯ 0.5). The positive allosteric effect of LY2033298 at the hM4 receptor was not unique to ACh, because it also selectively potentiated other full and partial orthosteric agonists, such as NEUROSCIENCE carbachol, oxotremorine-M, and McN-A343 (data not shown). To confirm that the allosteric effect detected
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