Austin NE

Branch CL

Brown JT

Buchanan KA

Davies CH

Forbes IT

Fry VAH

Hagan JJ

Herdon HJ

Jeggo R

Jones GA

Kew JNC

Langmead CJ

Mazzali A

Melarange R

Pardoe J

Patel N

Randall AD

Roberts C

Roopun A

Starr KR

Teriakidis A

Watson J

Whittington M

Wood MD

Wu Z

Background and purpose: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer\u27s 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 M 1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR. \ua9 2008 Nature Publishing Group All rights reserved

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

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

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