Project ID: D2022-18
Background
Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors that are located in the cell membranes of neurons and mediate the effects of the neurotransmitter acetylcholine (ACh). Each mAChR forms a complex with intracellular G proteins that, when activated, produce an intracellular signaling cascade. Each mAChR subtype features two types of ligand binding, via orthosteric and allosteric sites. The orthosteric site is primarily responsible for receptor activation by the endogenous ligand (ACh) and other orthosteric agonists. Ligand binding to allosteric sites results in modulation of receptor activity. The initial generations of proposed drugs that targeted mAChRs included ACh precursors, acetylcholinesterase inhibitors, and mAChR agonists which directly or indirectly activate receptors through interactions with the orthosteric binding site.
Many CNS disorders involve altered cholinergic signaling, and treatment of these disorders with subtype non-specific agents frequently results in adverse effects. In general, orthosteric ligands developed thus far exhibit poor selectivity between the different mAChR subtypes due to the location of orthosteric binding sites in highly conserved regions of mAChRs. Most M1 muscarinic receptor positive allosteric modulators (PAMs) developed thus far increase ACh potency (enhancing effects at low concentrations), yet few enhance the efficacy of ACh (increase overall receptor activity). Effective treatments for neurological disorders may require shaping neuronal signaling to fine-tune ACh activity beyond just enhancing potency. Thus, there is a need in the art for new subtype-selective ligands that enhance ACh efficacy.
Invention Description
Researchers developed positive allosteric modulators of muscarinic receptors that act by enhancing ACh efficacy; maximal responses to ACh are increased in the presence of such allosteric modulators. Preliminary data in zebrafish models suggest that the compounds penetrate into the brain and reduce repetitive behaviors; zebrafish treated with the novel compounds were found to have decreased repetitive behaviors, as measured by angular velocity and turn angle. The compounds also exhibit low toxicity in preliminary screens in zebrafish. The novel aspect of the technology is the allosteric modulation of efficacy, which could be particularly useful in enhancing memory consolidation and restoring ACh signaling in failed systems as found in a variety of neurological disorders.
Applications
Advantages