Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
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Sams AG, Larsen K, Mikkelsen GK, Hentzer M, Christoffersen CT, Jensen KG, Frederiksen K, Bang-Andersen B
Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.
Bioorg Med Chem Lett. 2012 Aug 1;22(15):5134-40. doi: 10.1016/j.bmcl.2012.05.048. Epub 2012 May 18.
- PubMed ID
- 22677319 [ View in PubMed]
- Abstract
We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydr o-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetylcholine Muscarinic acetylcholine receptor M1 EC 50 (nM) 1.1 N/A N/A Details Acetylcholine Muscarinic acetylcholine receptor M2 EC 50 (nM) 220 N/A N/A Details Acetylcholine Muscarinic acetylcholine receptor M3 EC 50 (nM) 3.2 N/A N/A Details Acetylcholine Muscarinic acetylcholine receptor M4 EC 50 (nM) 10 N/A N/A Details Haloperidol Dopamine D2 receptor Ki (nM) 3 N/A N/A Details