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.

Consequence of solubility alteration by salt effect on dissolution enhancement and biological response of a solid dispersion of an experimental antianginal drug.

Improvement of dissolution of a poorly water-soluble experimental antianginal drug has been obtained by solid dispersion preparation. Its solubility decreased with rising chloride ion concentration and biological responses in dogs varied with the gastrointestinal administration site. A correlation seemed to exist between the apparent solubility and the heart rate activity.

Dualist or pseudo-dualist interactions of mepyramine, diphenhydramine and eprozinol with histamine at H1-receptors.

The types of interaction of mepyramine (M), diphenhydramin: (D) and eprozinol (E), with histamine H1-receptors of guinea pig ileal and tracheal smooth muscle, were comparatively studied in vitro. According to the concentrations used, all three substances showed an apparent dualist mechanism of action on both preparations when histamine (dihydrochloride) was used as the agonist. The competitive component of this mechanism (at low concentrations) was characterized by the following pA2 values: 9.01 (M), 7.80 (D) and 5.64 (E) with the ileum; 8.06 (M), 7.00 (D) and 6.02 (E) with the trachea. The so called non specific component (at high concentrations) was of comparable intensity in the two organs. The pD'2 values were 5.54-5.66 (M), 4.65-4.38 (D) and 3.82-3.55 (E) with ileal and tracheal muscle, respectively. At low concentrations the equi-active dose-ratio for N/D/E (1/16/2300 on the ileum) became 1/12/110 when the trachea was used as the effector. This is surprising since histaminergic receptors of the two preparations are of the same H1-type. It is suggested that only diphenhydramine and eprozinol are really dualistic, and that the non-specific mechanism of activity differs for each drug with that of eprozinol being effective on tracheal muscle.

[Relation between the electronic structure of a series of 1,4-tetrahydro-oxazines and their p-D2, for the tryptaminergic receptor]. / Relation entre la structure électronique d'une série de 1.4-tétrahydro-oxazines et leur p-D2, vis-à-vis du réceptor tryptaminergique.

Certain features of the isopotential maps of morpholine derivatives seem to be related to their ability to bind with tryptaminergic receptors.

Accion del 5'-adenilato de heptaminol sobre el debito venoso del perro anestesiado y sobre la contractilidad del musculo liso vascular. / Effect of 5'-adenylate of heptaminol on the venous output of anesthetized dogs and on the contractility of vascular smooth muscle

Se estudiaron los efectos del 5'-adenilato de heptaminol (adenosin 5'-monofosfato + 6-amino-2-metil-2 heptanol o heptaminol) sobre el debito venoso del perro anestesiado y su posible antagonismo frente a los efectos contractiles de la fibra lisa. Se utilizaron 5 perros de raza comun a los que se les administro 0.5 mg/kg de la sustancia en estudio, y los parametros registrados fueron debito venoso iliaco externo, presion arterial sistemica y frecuencia cardiaca. Se investigo una interaccion con la serotonina sobre el musculo fundico del estomago de la rata, y una inhibicion de la respuesta contractil del musculo liso vascular consecutivo a una despolarizacion con potasio. Las diferencias experimentales y su significado estadistico fueron calculados por medio de la prueba "t" de Student-Fisher aplicada sobre las series apareadas