Glycinergic potentiation by some 5-HT3 receptor antagonists: insight into selectivity

The ability of various 5-HT3 receptor antagonists to potentiate spinal glyc ine responses was investigated. Whereas (3-alpha-tropanyl)-1H-indole-3-carb oxylate (ICS 205930), (3-alpha-tropanyl)-3,5-dichlorobenzoate (MDL 72222) a nd 1-methyl-N-(3-alpha-tropanyl)-1H-indazole-3-carboxamide (LY 278584) exhi bited this property, even in identified motoneurones, several other chemica lly similar 5-HT3 receptor antagonists did not. Introducing a methyl group on the nitrogen of the azabicyclo moiety of ICS 205930 greatly reduced the ability to potentiate glycine responses. Neither endo-1-methyl-N-(9-methyl- 9-azabicyclo[3.3.1]non-3-yl)-indazole-3-carboxamide (granisetron), differin g from LY 278584 by an additional carbon in this cycle, nor 2 beta-carbomet hoxy-3 beta-benzoyloxytropane (cocaine), 1,2,3,9-tetrahydro-9-methyl-3-[(2- methyl-1H-imidazol-1-yl)-methyl]-4H-carbazol-4-one (ondansetron) and (S)-4- amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methyoxy-benzamide ((S)-za copride) could potentiate glycine responses. A pharmacophore model of the g lycinergic potentiators was generated by molecular modelling using MDL 7222 2 as a template. According to this model, an aromatic ring, a carbonyl grou p and a tropane nitrogen atom are required for glycinergic potentiation, as previously described for 5-HT3 receptor antagonism. However, the steric al lowance at the glycine receptor site and the tridimensional arrangement of the pharmacophoric elements appear to be mon restricted. (C) 2000 Elsevier Science B.V. All rights reserved.