M.I. Martin

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.

Age-related changes in nociception, behavior, and monoamine levels in rats.

1. Pain threshold, behavioral parameters, and monoamine levels were compared in two groups of rats: adult (12 months old) and old rats (25 months old). 2. No differences in nociception were found between the two groups using the tail-shock test. 3. Behavioral experiments with the holeboard test showed that locomotor activity and exploration activity were lower in aged animals, whereas no significant differences were found in emotivity. 4. Using high-performance liquid chromatography (HPLC) techniques, we found that serotonin and dopamine showed lower levels in the old group.

Effect of Bay K 8644 on the synthesis and metabolism of dopamine and 5‐hydroxytryptamine in various brain areas of the rat

Abstract— The effects of Bay K 8644 (1,2 and 4 mg kg−1, i.p.) on the synthesis and metabolism of dopamine and 5‐hydroxytryptamine (5‐HT) in rat brain after m‐hydroxybenzylhydrazine administration were studied. Bay K 8644 (2 and 4 mg kg−1, i.p.) caused an increase in the synthesis of both dopamine in the striatum and 5‐HT in the midbrain and striatum, measured as the accumulation of 3,4‐dihydroxyphenylalanine (dopa) and 5‐hydroxytryptophan, respectively. Moreover, Bay K 8644 at the dose of 4 mg kg−1 increased the turnover of dopamine in the striatum and of 5‐HT in midbrain and striatum. These neurochemical changes were antagonized by the calcium channel antagonist nimodipine (10 mg kg−1, i.p.). It is concluded that dihydropyridine receptors may mediate the brain region‐specific changes in the dopaminergic and 5‐HT‐ergic neurotransmission which occur following activation of neuronal calcium channels.

In vitro study of the interaction of salmon calcitonin with μ, δ and κ opioid agonists

SummaryA possible interaction of salmon-calcitonin with opioid systems was studied in isolated tissues. Neurogenic contractions were elicited by electrical stimulation in guinea-pig ileum myenteric plexus-longitudinal muscle strips, rabbit vas deferens and mouse vas deferens.Bremazocine inhibited neurogenic contractions in all three tissues (presumably through κ-receptors) [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin inhibited contractions in mouse vas deferens (presumably through δ-receptors), and [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) inhibited contractions in guinea-pig ileum and mouse vas deferens (presumably through μ-receptors). All inhibitory effects were concentration-dependent. Salmon-calcitonin 0.1 IU/ml increased the effect of bremazocine in guinea-pig ileum and rabbit vas deferens and also increased the effects of [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin in mouse vas deferens. In contrast, salmon-calcitonin up to 0.4 IU/ml did not change the effect of bremazocine in mouse vas deferens and the effect of DAMGO in guinea-pig ileum and mouse vas deferens.It is concluded that salmon-calcitonin enhances agonist effects at opioid κ- and δ- but not at opioid μ-receptors. The level of this interaction remains to be elucidated. The interaction may be the basis of the analgesic effect of salmon-calcitonin in vivo.

Study of mechanisms of calcitonin analgesia in mice. Involvement of 5-HT3 receptors.

The analgesic effect of calcitonin when serotonin (5-HT) concentration is increased and the involvement of some 5-HT receptors were studied using the writhing test in mice. 5-hydroxytryptophan (5-HTP) administration increased both 5-HT levels in the central nervous system (CNS) and calcitonin analgesia. The 5-HT(1A) agonist (+/-)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) diminished calcitonin analgesia, this effect being antagonised by the 5-HT(1A) antagonist (WAY 100, 135). As the stimulation of 5-HT(1A) autoreceptors reduces the turnover of 5-HT, the effect of 8-OH-DPAT on calcitonin analgesia may be attributed to this decrease. The 5-HT(2A-2C) agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) diminished calcitonin analgesia. A sub-analgesic dose of the 5-HT(2A) antagonist ketanserin failed to prevent this effect. The 5-HT(3) agonist (+/-)-2-methyl-5-hydroxytryptamine maleate (2-methyl-5-HT) potentiated calcitonin analgesia, whereas it was significantly reduced by the 5-HT(3) antagonist tropisetron. The effect of 2-methyl-5-HT on calcitonin analgesia was also reversed by tropisetron, This result suggests that the 5-HT(3) receptor may play an important role in the relationship between calcitonin and the serotonergic system. Tropisetron also reversed the analgesia induced by calcitonin plus 5-HTP corroborating importance of the 5-HT(3) receptors.

Analgesic effect of two calcitonins and in vitro interaction with opioids

1. When the analgesic effect of salmon-calcitonin (S-CT) and of eel-calcitonin (E-CT), as well as their influence on the morphine-analgesia were compared, no significant differences were found. 2. While on isolated tissues, E-CT induced a significant increase on the effect of bremazocine, [D-Pen2,D-Pen5]enkephalin and [Met5]enkephalin and no changes were observed on the effect of DAMGO, suggesting that E-CT increases the effects of opioids acting on delta or kappa receptors but not on mu receptors. 3. These findings corroborate the possibility of interactions between calcitonin and the opioid system.

Effect of salmon-calcitonin on the analgesic effect of selective μ, δ and κ opioid agonists in mice

Abstract The analgesic effect of three different opioid agonists, DAMGO ([ d -Ala 2 , N -Me-Phe 4 ,Gly 5 -ol]enkephalin), U-50,488H ( trans -3,4-dichloro- N -methyl- N -[2-(1-pyrrolidynyl)cyclohexyl] benzene-aceramide methane sulphonate), and [ d ,Pen 2 - d ,Pen 5 ]-enkephalin, which act upon μ , δ and κ opioid receptors, respectively, was compared in the presence and absence of salmon-calcitonin (s-CT). The analgesic test used was the writhing test in mice. The analgesic effect of the opioids was significantly enhanced by pretreatment of the animals with s-CT intraperitoneally (i.p.) administered. This effect was more evident for the δ and κ -agonists. The present result suggests that the joint administration of s-CT and opioids may be a useful and interesting alternative in the treatment of painful diseases resistant to other treatments.

Influence of pertussis toxin on the calcitonin-opioid interaction in isolated tissues.

1 In order to clarify one of the mechanisms involved in the analgesic effect of calcitonin, we have tested the in vitro modifications induced by calcitonin on the effect of opioids. 2 The inhibition of the contractions induced by opioids or clonidine, in guinea‐pig ileum or in mouse vas deferens, were significantly reduced in tissues incubated with pertussis toxin (PTX). When tissues were incubated with PTX and calcitonin, the inhibitory effect was restored. 3 These results suggest that calcitonin is able to potentiate a non‐PTX‐sensitive mechanism of transduction and support the possibility of involvement of similar G‐proteins in the effects of opioid and α2‐adrenoceptor agonists.

Effect of butanedione monoxime on the contractility of guinea pig ileum and on the electrophysiological activity of myenteric S-type neurones

2,3-Butanedione monoxime (BDM) has demonstrated protective effects on isolated cardiac tissues, and on smooth muscle but its mechanism of action is not fully understood. To simultaneously study the effect of BDM on muscle contractility and on neuronal activity, the effect of BDM was tested in the contractile force of myenteric plexus-longitudinal muscle strips and in electrophysiological activity of myenteric S-type neurones of guinea pig ileum. BDM reduces, in a dose-dependent manner, the force of the spontaneous motility and the contractions induced by acetylcholine, bethanechol and electrical stimulation. The same BDM concentrations depolarize the neuronal membrane and reduce the rate of evoked firing. The effect of BDM can be attributed to a direct effect on the smooth muscle and to modifications of the neuronal activity.

Cholesterol-fed Rabbits: Study of the Response of the Vas Deferens to Adrenergic and Non-adrenergic Stimulus and to a K-Opioid Agonist

The aim of the present study was to analyse the contractility of the isolated vas deferens from hypercholesterolaemic rabbits; for this purpose we evaluated the contractile response induced by noradrenaline and by electrical stimulation.