2008
DOI: 10.1124/mol.108.050963
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Mutagenic Mapping Suggests a Novel Binding Mode for Selective Agonists of M1 Muscarinic Acetylcholine Receptors

Abstract: Point mutations and molecular modeling have been used to study the activation of the M 1 muscarinic acetylcholine receptor (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 with N-desmethylclozapine (NDMC) and acetylcholine (ACh). Unlike NDMC and ACh, the activities of AC-42 and 77-LH-28-1 were undiminished by mutations of Tyr404 and Cys407 (transmem… Show more

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Cited by 50 publications
(93 citation statements)
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“…Consistent with previous reports (15,22,23), improved binding of TBPB and 77-LH-28-1 was detected at the W101 3.28 A receptor. This was also observed for the agonist fragment derivative of TBPB (VCP794), and all three ligands exhibited improved binding at the Y381 6.51 A receptor (Fig.…”
Section: Effects Of Mutations On Expression Of the M 1 Machr-satusupporting
confidence: 82%
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“…Consistent with previous reports (15,22,23), improved binding of TBPB and 77-LH-28-1 was detected at the W101 3.28 A receptor. This was also observed for the agonist fragment derivative of TBPB (VCP794), and all three ligands exhibited improved binding at the Y381 6.51 A receptor (Fig.…”
Section: Effects Of Mutations On Expression Of the M 1 Machr-satusupporting
confidence: 82%
“…In comparison, the efficacy of 77-LH-28-1-activated pERK1/2 was reduced at the F77 2.56 I mutant (Fig. 10C), consistent with previous reports (15,22,23). However, its efficacy in [Ca 2ϩ ] i mobilization experiments was unchanged (Fig.…”
Section: E2supporting
confidence: 81%
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