1. Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1.
- Author
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Langmead, C. J., Austin, N. E., Branch, C. L., Brown, J. T., Buchanan, K. A., Davies, C. H., Forbes, I. T., Fry, V. A. H., Hagan, J. J., Herdon, H. J., Jones, G. A., Jeggo, R., Kew, J. N. C., Mazzali, A., Melarange, R., Patel, N., Pardoe, J., Randall, A. D., Roberts, C., and Roopun, A.
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MUSCARINIC receptors ,TARGETED drug delivery ,ALZHEIMER'S disease ,SCHIZOPHRENIA ,ALLOSTERIC regulation ,OSCILLATING chemical reactions ,INOSITOL phosphates ,ELECTROPHYSIOLOGY - Abstract
Background and purpose:M
1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M1 mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs.Experimental approach:In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology.Key results:Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration.Conclusions and implications:These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.British Journal of Pharmacology (2008) 154, 1104–1115; doi:10.1038/bjp.2008.152; published online 5 May 2008 [ABSTRACT FROM AUTHOR]- Published
- 2008
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