Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1

Christopher J Langmead, Nigel E Austin, Clive L Branch, Jon T Brown, Katherine A Buchanan, Ceri H Davies, Ian T Forbes, Victoria Anne Honey Fry, Jim Joseph Hagan, Hugh J Herdon, Gareth A Jones, Ross David Jeggo, James N C Kew, Angelica Mazzali, Rosemary A Melarange, Nisha Patel, Joanne Pardoe, Andrew D Randall, Claire Jane Roberts, Anita K RoopunKathryn R Starr, Adrianna Teriakidis, Martyn D Wood, Miles Adrian Whittington, Zining Wu, Jeannette M Watson

Research output: Contribution to journalArticleResearchpeer-review

97 Citations (Scopus)

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 M 1 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 M 1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M 1 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 M 1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M 1 mAChR.
Original languageEnglish
Pages (from-to)1104 - 1115
Number of pages12
JournalBritish Journal of Pharmacology
Volume154
Issue number5
DOIs
Publication statusPublished - 2008
Externally publishedYes

Cite this