[AC-42: Mutagenic mapping suggests a novel binding mode for selective agonists of M1 muscarinic acetylcholine receptors]
Mol Pharmacol. 2008 Nov 11. [Epub ahead of print]
Mutagenic mapping suggests a novel binding mode for selective agonists of M1 muscarinic acetylcholine receptors.
Lebon G, Langmead CJ, Tehan BG, Hulme EC.
National Institute for Medical Research.
Point mutations and molecular modelling have been used to study the activation of the M1 muscarinic acetylcholine receptor (M1 mAChR ) by the functionally-selective agonists 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine (AC-42), and 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone (77-LH-28-1), comparing them to N-desmethylclozapine (NDMC) and ACh. Unlike NDMC and ACh, the activities of AC-42 and 77-LH-28-1 were undiminished by mutations of Tyr404 and Cys407 (transmembrane helix 7), although reduced by mutations of Tyr408. Signalling by AC-42, 77-LH-28-1 and NDMC was reduced by Leu102Ala and abolished by Asp105Glu, suggesting that all three may interact with transmembrane helix 3 at or near the binding site Asp105, to activate the M1 mAChR. In striking contrast to NDMC and ACh, the affinities of AC-42 and 77-LH-28-1 were increased 100-fold by Trp101Ala , and their signalling activities abolished by Tyr82Ala. Tyr82 and Leu102 contact the indole ring of Trp101 in a structural model of the M1 mAChR. We suggest the hypothesis that the side-chain of Trp101 undergoes conformational isomerisation, opening a novel binding site for the aromatic side-chain of the AC-42 analogues. This may allow the positively-charged piperidine nitrogen of the ligands to access the neighbouring Asp105 carboxylate to activate signalling, following a vector within the binding site that is distinct from that of acetylcholine. NDMC does not appear to use this mechanism. Subtype-specific differences in the free energy of rotation of the side-chain and indole ring of Trp101 might underlie the M1-selectivity of the AC-42 analogues. Trp conformational isomerisation may open up new avenues in selective muscarinic receptor drug design.<<
Just parking. AC-42 has been mentioned in other articles before, going back to at least 2002, and is likely dead as a commercial prospect. Not that you'd know from Acadia's non-existent pipeline chart. This is a full text freebie, and if one is interested, the full article is available here:
molpharm.aspetjournals.org
Cheers, Tuck |
