Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic m1 receptor activation.

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Sauerberg P, Jeppesen L, Olesen PH, Sheardown MJ, Fink-Jensen A, Rasmussen T, Rimvall K, Shannon HE, Bymaster FP, DeLapp NW, Calligaro DO, Ward JS, Whitesitt CA, Thomsen C

Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic m1 receptor activation.

Bioorg Med Chem Lett. 1998 Oct 20;8(20):2897-902.

PubMed ID
9873644 [ View in PubMed
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Abstract

Series of analogs to the functional m1 selective agonist, xanomeline (hexyloxy-TZTP), were evaluated for their in vitro m1 efficacy in cell lines transfected with the human m1 receptor. Systematic variation of the side chain and the azacyclic ring led to the discovery of potent muscarinic agonists with robust m1 efficacy, all having the phenylpropargyloxy/thio as the side chain. The most selective compound was the phenylpropargylthio-[3.2.1] endo analog 28, which is a potent and efficacious m1 agonist with no m2 activity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ArecolineMuscarinic acetylcholine receptor M1EC 50 (nM)5603N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M1EC 50 (nM)3811N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M2EC 50 (nM)700N/AN/ADetails
PilocarpineMuscarinic acetylcholine receptor M1EC 50 (nM)8792N/AN/ADetails
PilocarpineMuscarinic acetylcholine receptor M2EC 50 (nM)63000N/AN/ADetails