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4(5)-(2,2-diphenylethyl)imidazole 6a is described as being a potent (pKi = 8.16 for displacement of [3H] p-amino-clonidine) and selective (selectivity = -log (pKiα2 - pKi α1) = 81)α2-adrenoreceptor antagonist (pA2 = 8.73 versus clonidine in the electrically stimulated guinea pig ileum) with additional activity as a norepinephrine uptake inhibitor (IC50 = 0.3 μM). An investigation of the structure-activity relationships of compounds closely related to 6a has been carried out. This included substitution of the phenyl and imidazole rings and modification of the link between these two ring systems. The various synthetic routes used are described. The affinity and the selectivity of the compounds for the α2 site were determined by studying the displacement of [3H] p-aminoclonidine and [3H] WB-4101 from rat forebrain membranes. The efficacy of the compounds was defined by measuring the antagonism of the clonidine effect on the electrically stimulated guinea pig ileum.

Les proprietes pharmacologiques de dix alcaloides tertiaires, hybrides et quaternaires extraits de Strychnos usambarensis ont ete examinees. Un alcaloide tertiaire, l'usambarensine, inhibe les effets muscariniques de l'acetylcholine sur l'ileon isole de rat. Quatre derives ammoniums quaternaires, la dihydrotoxiferine, l'afrocurarine (substance nouvelle), la curarine et la calebassine sont des agents curarisants tres actifs.The pharmacological properties of ten tertiary, hybrid and quaternary alkaloids isolated from the barks of Strychnos usambarensis roots have been investigated. Usambarensine, a tertiary amine derivative, inhibits the muscarinic effects of acetylcholine. Four ammonium quaternary products, dihydrotoxiferine, afrocurarine (a new substance), curarine and calebassine are potent curarizing agents.

The chemical separation and identification of ten alkaloids extracted from the roots of Strychnos usambarensis are described. The elucidation of their structure by means of elementary analysis, I. R., U.V, and mass spectrometry allows their classification into bistertiary amines, hybrid and bisquaternary ammonium derivatives. This classification is reflected in the pharmacological properties. One of the tertiary amine alkaloids (usambarensine) presents atopine-like and spasmolytic activities while the bisquaternary ammonium compounds (dihydrotoxiferine, calebassine, C-curarine and afrocurarine) are competitive neuromuscular blocking agents.

The vasorelaxing effect of suloctidil was evaluated in isolated rat and rabbit aorta and in isolated rabbit mesenteric and saphenous artery. Suloctidil inhibited contractions induced by increasing extracellular calcium in depolarized arteries, mainly in a competitive way. In the rat aorta, the pA2 value was 7.50 for suloctidil, while pA2 values of 9.96, 7.90 and 8.10 were obtained for nifedipine, cinnarizine and verapamil, respectively. Suloctidil more potently inhibited calcium-induced contractions in small arteries (mesenteric and saphenous artery), than in the aorta. Suloctidil also reduced the tonic component of the responses to norepinephrine. In contrast to the effects on calcium-induced contractions, the effects of suloctidil on norepinephrine-induced responses was mainly noncompetitive. In addition, and unlike cinnarizine and verapamil, high concentration of suloctidil also reduced the phasic component of contractile responses to norepinephrine. Furthermore, unlike nifedipine, verapamil, diltiazem and cinnarizine, suloctidil was devoid of a negative inotropic effect in spontaneously beating guinea-pig atria. In conclusion, suloctidil behaves as a Ca2+-channel blocker in arteries and displays an additional mode of action that could include receptor-operated Ca2+-channels or an intracellular site of action. In addition, suloctidil was found to affect small arteries more than the aorta, and not to affect the atria.

The anticonvulsant activity of a new drug, milacemide (2-(pentylamino)-acetamide), has been studied in animal models of convulsions like those induced by bicuculline, pentylenetetrazol, picrotoxin, strychnine, inhibitors of GABA synthesis as 3-mercaptopropionic acid, allylglycine, isoniazid and thiosemicarbazide and electroshock. Milacemide is particularly effective in inhibiting the convulsions induced by bicuculline. The ED50 is 5.7 mg/kg by oral route and the activity lasts for more than 48 hr. It is less active against pentylenetetrazol and only marginally active against electroshock. It has not be found active against the other types of convulsions. Milacemide has a low toxicity (LD50: 2585 mg/kg in the mouse) and alters the behaviour of mouse, rat and monkey, only at high doses (greater than or equal to 1000 mg/kg). Milacemide seems to be specially free of sedative potential.

1. Sarmentogenin, bipindogenin and their corresponding xylosides have been identified in the defensive secretion of Chrysolina herbacea. 2. The qualitative and quantitative compositions of the secretions of C. herbacea and C. coerulans are compared. 3. The cardiotonic and cardiotoxic activities of sarmentogenin xyloside have been measured on guinea-pig left atria, and found to be somewhat higher than those of digoxin and comparable to those of ouabain. 4. It is suggested that the prime protection of the insects is due to the bitterness of the highly concentrated secretion (100–200 μg cardenolides/μl).

The effect of tibalosine (CP 804 S) on systolic blood pressure and heart rate of unanaesthetized normotensive, spontaneously hypertensive (SHR) and DOCA-salt and Goldblatt hypertensive rats has been examined. After a single oral dose, tibalosine (1.9 to 15 mg/kg) elicited dose-dependent reductions in blood pressure in the four models tested. These reductions are accompanied by a tachycardia except in the SHR where no variation in heart rate is observed. The same result is obtained in SHR after oral, i.v. or i.c.v. administration. After repeated treatment (9 to 14 weeks), the blood pressure lowering effect of tibalosine (10 mg/kg, p.o.) is observed only in hypertensive rats. No variation in heart rate is observed in normotensive, DOCA-salt and Goldblatt rats. A significant bradycardia is observed in the SHR. The antihypertensive effect of tibalosine in SHR is suppressed by naloxone, like that of clonidine and unlike that of prazosin. The present study suggests that the antihypertensive activity of tibalosine is at least partly centrally mediated.

The potentiation of the noradrenaline (NA) actions by antidepressant drugs was studied in vitro on the rat vas deferens and in vivo on the rat blood pressure. A new dibenzazepine compound, LM 208, and two antiparkinsonian drugs, orphenadrine and its demethylated derivative, were compared to well known antidepressants. The modification by all these agents of the rat uterus response to 5-hydroxytryptamine (5-HT) was also investigated. The possible use of these interactions as models for NA and 5-HT uptake inhibition is discussed.