CONFORMATIONALLY CONSTRAINED ANALOGS OF THE MUSCARINIC AGONIST IADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE - SYNTHESIS, RECEPTOR AFFINITY, AND ANTINOCICEPTIVE ACTIVITY

Conformationally constrained analogues of the potent muscarinic agonis t iadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (methylthio-TZTP, 17) were designed and synthesized with the aim of (a) improving the a ntinociceptive selectivity over salivation and tremor and (b) predicti ng 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-C 3-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 a s being the active conformations. The analogues were tested for centra l muscarinic receptor binding affinity, for their antinociceptive acti vity in the mouse grid shock test, and, in the same assay, for their a bility to induce tremor and salivation. The data showed that the tricy clic 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 ha s a C3-C4-C3'-N2' dihedral angle close to 180 degrees.