Angela Alsasua

New aromatic iminoimidazolidine derivatives as α1-adrenoceptor antagonists: a novel synthetic approach and pharmacological activity

The design, synthesis and alpha1-adrenoceptor antagonism of a series of bis-imidazoline (1a, 2a, 3a and 4a) and bis-guanidine (1b, 2b, 3b and 4b) diphenyl derivatives are reported. All of these compounds fulfill the conditions of the most recent pharmacophore proposed for alpha1-adrenoceptors and found in the literature. Besides, a novel synthetic approach to the preparation of 2-(arylimino)imidazolidine derivatives is described. All the tested compounds, except the bis-guanidinium derivative 3b, inhibit the contractile responses induced by noradrenaline in aortic rings of rat and rabbit in a dose-dependent manner. Our results indicate that, even though some discrepancies are observed in terms of the alpha1 subtype targeted by this new family of compounds, they show an interesting profile as antagonists of alpha1-adrenoceptors and a new prototype, compound 1a, has been found deserving further development.

μ- and δ-opioid receptor-mediated contractile effects on rat aortic vascular smooth muscle

The actions of opioid receptor agonists and antagonists were studied in isolated rat aortic strips. Morphine (10(-7)-10(-6) M) had no contractile effect on resting strips but when added during the relaxation of the contractions induced by 10(-9) M noradrenaline, it induced a contractile response which was blocked by naloxone. The selective mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO, 10(-7)-10(-6) M), induced an increase in basal tension which remained after removal of endothelium or in Ca(2+)-free solution, but was inhibited by beta-flunaltrexamine. beta-Flunaltrexamine also inhibited the contractile response induced by DAMGO added during the relaxation of the contractions induced by noradrenaline. The delta-opioid receptor agonist, [D-Pen2,D-Pen5]enkephalin, had no effect on resting tension but potentiated the contractions induced by noradrenaline; these effects were abolished by naltrindol. The selective kappa-opioid receptor agonist, bremazocine, had no effect on resting tension and did not modify the amplitude of the contractions induced by noradrenaline. These results suggest that, at low concentrations, agonists of mu- and delta-opioid receptors may act as modulators of noradrenaline-induced responses, whereas at higher concentrations, mu-opioid receptor stimulation may have a direct contractile effect in isolated rat aorta.

The involvement of 5-HT3 and 5-HT4 receptors in two models of gastrointestinal transit in mice.

Our aim was to study the involvement of 5-hydroxytryptamine (5-HT)(3) and 5-HT(4) receptors in two models of gastrointestinal transit (GIT) in mice: the 5-hydroxytryptophan (5-HTP)-induced diarrhea and intestinal inflammation produced by an irritant agent, croton oil (CO). 5-HTP (10 mg/kg) produced diarrhea that was significantly inhibited after pretreatment with ondansetron (5-HT(3) antagonist) or RS 39604 (5-HT(4) antagonist) (1-5 mg/kg). The GIT speed was increased after CO and 5-HTP administration. 5-HT(3-4) antagonists decreased GIT after 5-HTP-treatment but not after CO-treatment. Our results show that 5-HT(3) and 5-HT(4) receptors are involved in 5-HTP-induced diarrhea. This may be the reason why 5-HT(3-4) antagonists could be useful in the treatment of carcinoid syndrome diarrhea. 5-HT(3-4) antagonists were not effective in the modifications of GIT; nevertheless, they could be useful in the treatment of inflammatory bowel diseases because some symptoms as abdominal pain, discomfort or abnormal bowel function are modulated via 5-HT(3).

Vascular alterations in rats with high blood pressure induced by social deprivation stress.

While an activation of the opioid system has been found to play a role only in the triggering of the high blood pressure induced by brief (7-14 days) social deprivation stress in Wistar rats, factors responsible for the maintenance of the hypertension after long-term (30-35 days) isolation remained to be elucidated. To this aim, the effects of social deprivation stress on the functional and morphological features of blood vessels were studied. The tail artery, as a muscular vessel, and the aorta, as a large elastic vessel were used in these experiments. In ex vivo experiments, aorta and tail artery strips from rats isolated for 30-35 days were found to be hyperreactive to noradrenaline.

New benzimidazole derivatives: selective and orally active 5-HT3 receptor antagonists

The synthesis of new 5-HT(3) receptor antagonists is an interesting field of research because of their wide therapeutic use. The aim of this work is to functionally characterise a new series of benzimidazole derivatives previously described. These compounds bind to 5-HT(3) receptors and have been evaluated using in vitro (rat tunica muscularis mucosae) and in vivo tests (Bezold-Jarisch reflex in rat and gastrointestinal motility and spontaneous motility in mice). Ondansetron and 1-[4-amino-5-chloro-2-(3,5-dimethoxyphenil)methyloxy]-3-[1-[2-methylsulfonylamino]piperidin-4-yl]propan-1-one hydrochloride (RS 39604) were used as well known 5-HT(3) and 5-HT(4) receptor antagonists. These benzimidazole derivatives have proved to be 5-HT(3) receptor antagonists. Interestingly, they are as active as ondansetron when they are intraperitoneally (i.p.) or orally (p.o.) administered and, in mice, they seem to induce fewer behavioural changes at similar effective doses than does ondansetron. The present results confirm the usefulness of the previously proposed pharmacophore and justify the interest in these new benzimidazole derivatives.