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Milligan G, Kellett E, Dacquet C, Dubreuil V, Jacoby E, Millan MJ, Lavielle G, Spedding M: S 14506: novel receptor coupling at 5-HT (1A) receptors. . Neuropharmacology. 2001 Mar;40(3):334-44.
S 14506 is chemically related to the inverse agonist at 5-HT (1A) receptors, spiperone, but S 14506 behaves as one of the most potent agonists known at these receptors, both in vitro and in vivo. In hippocampal membranes, the specific binding of [(3) H]-S 14506 (K (d)=0.79+/-0.2 nM; B (max)=400+/-32 fmol/mg protein) to 5-HT (1A) receptors resembled that of an antagonist in that it was increased by GppNHp, whereas GppNHp reduced the binding of the classic agonist [(3) H]-8-OH-DPAT (K (d)=1.5+/-0.5 nM; B (max)=303+/-20 fmol/mg protein). Manganese, magnesium and calcium reduced the binding of [(3) H]-S 14506 to 5-HT (1A) receptors whereas the binding of [(3) H]-8-OH-DPAT was increased. Further, sodium markedly reduced the binding of [(3) H]-8-OH-DPAT, without affecting the binding of [(3) H]-S 14506. [(3) H]-S 14506 also bound with high affinity to h 5-HT (1A) receptors stably expressed in membranes of CHO cells (K (d)=0.13+/-0.05 nM; B (max)=2.99+/-0.60 pmol/mg protein): the B (max) was double that of [(3) H]-8-OH-DPAT. GppNHp strongly decreased [(3) H]-8-OH-DPAT binding but scarcely changed [(3) H]-S 14506 binding; calcium, magnesium and manganese had little effect on [(3) H]-S 14506 binding in CHO cells. Antagonists (WAY 100635, WAY 100135) and inverse agonists (spiperone and metitepine) displaced [(3) H]-S 14506 binding with high affinity and Hill slopes close to unity, whereas agonists (5-HT and 5-CT) displayed low affinity with low Hill slopes: partial agonists (buspirone, ipsapirone) showed intermediate properties. In fusion proteins of h 5-HT (1A) receptors with G (ialpha1) the compound potently increased high-affinity GTPase, with a steeper Hill slope than for 5-HT, which may indicate positive cooperativity. The maximum response for S 14506 in these assays was equivalent to 5-HT, indicating it to be a full agonist.In molecular modelling studies, using a three-site model of the 5-HT (1A) receptor, S 14506 spanned between the 5-HT recognition site and the "arginine switch" (DRY microdomain) postulated to activate the interaction of the receptor with the G protein. Thus it is possible to synthesise ligands at G-protein-coupled receptors which are highly potent agonists, but which are structurally related to inverse agonists and show some features of antagonist/inverse agonist binding. |
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