The antagonist properties of S 11978 on 5HT3 receptors in N1E-115 neuroblastoma cells.

The effects of the novel antagonist S 11978 (Endo-7-[(8-methyl-8-azabicyclo[3,2,1]-3-octyl)oxycarbonyl] benzo[b] thiophene) on 5HT3 receptors were examined in N1E-115 mouse neuroblastoma x rat glioma hybrid cells, with radioligand binding and whole cell patch clamp techniques. The 5HT3 receptor ligand [3H] quipazine was displaced by ICS 205-930, GR 38032F and S 11978 with KI values of 2.25 nM, 36.5 nM and 1.75 nM respectively. Electrophysiological studies showed that S 11978 is a potent 5HT3 antagonist: IC50 values for inhibition of 5HT-induced inward current by ICS 205-930, GR 38032F and S 11978 were 0.22 nM, 0.63 nM and 0.43 nM respectively at a holding potential of -65 mV. It is concluded that S 11978 is a potent, high affinity 5HT3 receptor antagonist.

Structure-activity relationships of tricyclic antidepressants, with special reference to tianeptine.

Structure-activity relationships in the classical antidepressant (imipramine-like) series show a relative lack of specificities: Compounds should simply have a nucleus consisting of two phenyl rings and a third, seven-member central ring. This central ring may have one, several, or no heteroatoms, and it may or may not be saturated. The side chain may be attached to any one of the atoms of the central ring, but it must be short (two or three carbon atoms), and have a terminal amine group (secondary, tertiary, or included in a ring). We investigated the structure-activity relationships of 22 new tricyclic tianeptine derivatives exhibiting reserpine-induced ptosis reversal potency in the mouse. Tianeptine is an antidepressant characterized by a 3-chlorodibenzothiazepin nucleus and an aminoheptanoic side chain. Our results indicate highly specific structural requirements for the tianeptine-like series. In order to be active, compounds must have an aminocarboxylic chain (with an optimal length of six methylene links), a tricyclic system with an electron-donor heteroatom in position 5, and an aromatic substitution with a moderate electron-acceptor atom in position 3. These specificities in the tianeptine series are in sharp contrast with the lack of specific requirements that characterize the classical tricyclic series.

Fenfluramine and 5-hydroxytryptamine?. Part 1: Is fenfluramine or norfenfluramine involved in the decrease of brain 5-hydroxytryptamine.

Both fenfluramine and de-ethylated fenfluramine decrease the brain stores of 5-hydroxytryptamine (5-HT). As the fenfluramine metabolite is present in the brain of the rat after fenfluramine injection, it could be suggested that the depletion of brain 5-HT elicited by fenfluramine is mediated by its metabolite. Comparative studies on 5-HT lowering effects and drug brain levels, indicate a primary effect of fenfluramine, following by the rising involvement of the de-ethylated compound in the sustained effect.

Fenfluramine and 5-hydroxytryptamine. Part 2: Involvement of brain 5-hydroxytryptamine in the anorectic activity of fenfluramine.

As it is well-known, fenfluramine produces anorexia and decrease in brain 5-hydroxytryptamine (5-HT). As it has been suggested that the anorectic effect of fenfluramine may be due to a release of brain 5-HT, we have examined the influence of several drugs active on 5-HT mechanisms and metabolism, on the anorexigenic activity of fenfluramine. These studies were made in relationship with the depletion of 5-HT levels and the concentration of brain fenfluramine or m-trifluoromethyl-isopropylamine. The results have confirmed the involvement of a tryptaminergic mechanism in fenfluramine anorexia and suggest the hypothesis that fenfluramine itself can interfere with the serotoninergic system in the brain (stimulation of tryptaminergic neurons directly).