Conformationally constrained analogues of the muscarinic agonist 3-(4-(methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyr idine. Synthesis, receptor affinity, and antinociceptive activity.

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Sauerberg P, Olesen PH, Sheardown MJ, Rimvall K, Thogersen H, Shannon HE, Sawyer BD, Ward JS, Bymaster FP, DeLapp NW, Calligaro DO, Swedberg MD

J Med Chem. 1998 Jan 1;41(1):109-16.

PubMed ID

9438027 [ View in PubMed

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Abstract

Conformationally constrained analogues of the potent muscarinic agonist 3-(4-methylthio)-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methy lpyridine (methylthio-TZTP, 17) were designed and synthesized with the aim of (a) improving the antinociceptive selectivity over salivation and tremor and (b) predicting the active conformation of 17 with respect to the dihedral angle C4-C3-C3'-N2'. Using MOPAC 6.0 tricyclic analogues (7, 15, 16) with C4-C3-C3'-N2' dihedral angles close to 180 degrees and a rotation hindered analogue (9) with a C4-C3-C3'-N2' dihedral angle close to 274 degrees were designed, as these conformations had previously been suggested as being the active conformations. The analogues were tested for central muscarinic receptor binding affinity, for their antinociceptive activity in the mouse grid shock test, and, in the same assay, for their ability to induce tremor and salivation. The data showed that the tricyclic analogues (7, 15, 16) were equipotent with 17 as analgesics, but with no improved side effect profiles. The rotation-hindered analogue 9 had neither muscarinic receptor binding affinity nor antinociceptive activity. These results suggest that the active conformation of 17 has a C3-C4-C3'-N2' dihedral angle close to 180 degrees.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Arecoline	Muscarinic acetylcholine receptor M1	IC 50 (nM)	145000	N/A	N/A	Details
Arecoline	Muscarinic acetylcholine receptor M3	IC 50 (nM)	58000	N/A	N/A	Details