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C Melchiorre

Publications and source records attributed to C Melchiorre.

At least 73 records · Page 4Linked to original sources
PubMed1988

Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo.

The antimuscarinic effects of methoctramine (N, N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, 8-octanediamine tetrahydrochloride), a polymethylene tetraamine endowed with high cardioselectivity in vitro, were assessed in two in vivo preparations. Methoctramine (300 micrograms/kg i.v.) strongly inhibited the methacholine- and muscarine-induced bradycardia in the anaesthetized an pithed rat, respectively. The same dose of methoctramine did not significantly affect the depressor action of methacholine in the anaesthetized rat mediated by vascular M2 receptors. Furthermore, even high doses of methoctramine (up to 1 mg/kg i.v.) did not reduce the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343 in the pithed rat. These data suggest that methoctramine while showing high affinity for cardiac M2 alpha receptors has rather low affinity for ganglionic M1 and vascular M2 receptors. This in vivo study thus provides further evidence to support the view that methoctramine is a potent and highly selective antagonist of cardiac M2 alpha receptors.

Animals↗
PubMed1988

Structure-activity relationships among benextramine-related tetraamine disulfides. Chain length effect on alpha-adrenoreceptor blocking activity.

Several N'-substituted N,N''-(dithiodi-2,1-ethanediyl)bis(1, omega-alkanediamines) were prepared and evaluated for their blocking activity on alpha-adrenoreceptors in the isolated rat vas deferens and human blood platelets. The results were compared with those obtained for benextramine (N,N''-(dithiodi-2,1-ethanediyl)bis[N'-[(2-methoxyphenyl)-methyl]- 1 ,6- hexanediamine], 10). Bendotramine (N,N''-(dithiodi-2,1-ethanediyl)bis[N'-[(2-methoxyphenyl)- methyl]-1,12-dodecanediamine], 16) proved to be as active as 10 on alpha 1-adrenoreceptors, showing that optimum activity is associated with two carbon chain lengths separating inner from outer nitrogens of tetraamine disulfides. On the other hand, 16 had no activity up to 20 microM at alpha 2-adrenoreceptors. The optimum activity at this receptor subtype was associated with a six to eight carbon chain (10-12). Furthermore, 10 proved to be more selective toward alpha 2-adrenoreceptors whereas 16 was a selective alpha 1-antagonist. The tetraamine disulfides were shown also to be potent inhibitors of human platelet aggregation induced by ADP or epinephrine. The potency increased with the carbon chain length. However, the results on platelets did not parallel those found in the rat vas deferens, indicating that differences exist between the alpha-adrenoreceptor subtypes investigated. In conclusion, 10 may be a useful tool in characterizing alpha 2-adrenoreceptors whereas 16 might help in investigating alpha 1-adrenoreceptors.

Adenosine Diphosphate↗
PubMed1988

Structure-activity relationships in 1,4-benzodioxan-related compounds. Investigation on the role of the dehydrodioxane ring on alpha 1-adrenoreceptor blocking activity.

Several analogues of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxa n (WB 4101, 1) were prepared and evaluated for their blocking activity on alpha 1- and alpha 2-adrenoreceptors in the isolated rat vas deferens. The results were compared with those obtained for 1 and benoxathian (2). It was shown that the two oxygens at positions 1 and 4 may have a different role in receptor binding. It seems that the oxygen at position 4 as such does not contribute to the binding while it is important in stabilizing an optimal conformation for drug-receptor interaction mechanism. On the other hand, the oxygen at position 1 might interact with a receptor polar pocket of reduced size by way of a donor-acceptor dipolar interaction. Furthermore, it was shown that replacement of the dehydrodioxane ring of 1 by a phenyl or a pyrrole nucleus causes a significant decrease in activity.

Adrenergic alpha-Antagonists↗
PubMed1988

Binding and functional characterization of the cardioselective muscarinic antagonist methoctramine.

The antimuscarinic properties of the newly synthetized polymethylene tetramine derivative, methoctramine, were investigated in binding and functional assays. Methoctramine displaced the specific binding of [3H]-N-methylscopolamine [( 3H]NMS) and [3H] pirenzepine from membranes of rat tissues with the following order of affinities: heart = cerebellum greater than cortex greater than submandibular glands, the ratio of the affinities of the compound for the heart and the glands amounting to about 130. Computer fits of binding curves generated in cardiac and cortical membranes were compatible with an interaction at one binding site, whereas those in submandibular glands and cerebellum had slopes significantly lower than 1. Experiments performed in cardiac membranes to investigate the effect of methoctramine on the dissociation kinetics of [3H]-NMS showed that concentrations of compound up to 1 microM did not affect the dissociation of [3H]-NMS elicited by an excess of NMS. At greater concentrations (10-100 microM), methoctramine dose dependently inhibited [3H]-NMS dissociation, thus revealing an allosteric interaction. In in vitro functional assays, methoctramine displayed more than 100 times greater affinity for the muscarinic receptors mediating negative inotropic and chronotropic effects in guinea pig atria than for those responsible for tracheal contraction. Similarly, the compound was a more potent antagonist of the bradycardial response to bethanechol than of the bladder tonus increase, saliva secretion and hypotension induced by the muscarinic agonist in anesthetized cats. Finally, in the pithed rat, methoctramine preferentially inhibited cardiac M2 (vagal bradycardia) over ganglionic M1 (McN-A-343-induced hypertension) responses. The evidence appears to characterize methoctramine as being the most selective M2 muscarinic antagonist described to date.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine.

The antimuscarinic effects of methoctramine (N,N'-bis[6- [(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine tetrahydrochloride) were investigated in vitro in isolated paced left (force) and spontaneously beating right (force and rate) atria of guinea pigs as well as ileum of guinea pig and rat. Methoctramine was a potent competitive antagonist of M-2 muscarinic receptors in myocardium and pacemaker cells over a wide range of concentrations. The pA2 values ranged from 7.74 to 7.93. They were not significantly different in the two cardiac preparations and were independent of the agonist used (muscarine and carbachol). A combination of methoctramine with atropine resulted in addition of the dose ratios for left atria, which is expected for two antagonists interacting competitively with the same receptor site. In contrast, a combination of methoctramine with gallamine produced a less than additive shift of the dose-response curve for carbachol, confirming that gallamine acts as an allosteric antagonist at cardiac muscarinic receptors. Methoctramine was 54 to 132-fold less potent in ileal than in atrial preparations (pA2 values ranging from 5.81 to 6.20) which makes it the most cardioselective antimuscarinic agent now available. A combination of methoctramine with atropine gave a slight supra-additive antagonism on guinea pig ileum, which suggests that methoctramine interacts to some extent with a second independent site. These results strongly reinforce the view that M-2 muscarinic receptors are not a homogeneous population.

Animals↗
PubMed1987

Selective blockade in vivo of cardiac muscarinic M2 receptors by a polymethylene tetramine, BHC-9C.

The antimuscarinic effects of BHC-9C (N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1,9-nonanediamine tetrahydrochloride), a member of a series of polymethylene tetraamines with unprecedented in vitro selectivity for cardiac muscarinic M2 receptors, were assessed in several in vivo test systems. BHC-9C (300 micrograms/kg i.v.) proved to be a potent antagonist at cardiac M2 receptors that mediate the decrease in heart rate in the pithed rat. In contrast, it displayed no considerable blocking activity at vascular M2 receptors subserving vasodepression and at ganglionic M1 receptors that mediate cardiovascular stimulation in the anaesthetized and pithed rat, respectively. These in vivo data are consistent with the suggestion based on in vitro experiments that BHC-9C is a highly selective antagonist of cardiac muscarinic M2 receptors.

Anesthesia↗
PubMed1987

Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors.

Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.

Animals↗
PubMed1986

Thiol group may be involved in the irreversible blockade of presynaptic alpha 2-adrenoreceptors by pyrextramine and benextramine in the isolated guinea pig ileum.

This study, conducted on isolated guinea pig ileum, was designed to establish the mechanism of presynaptic alpha 2-adrenoreceptor blockade by the tetramine disulfides, benextramine and pyrextramine. At 1 microM these drugs irreversibly blocked norepinephrine (NE)-induced inhibition of the twitch response to electrical stimulation. This may be the result of covalent bond formation between the disulfide bridge of the inhibitor and a thiol function at the receptor level through an interchange reaction since the benextramine carbon analogue did not affect NE response under the same conditions. Furthermore, NE (10 microM) failed to protect presynaptic alpha 2-adrenoreceptors from pyrextramine blockade whereas idazoxan (O.T microM) completely abolished the irreversible antagonism of pyrextramine (1 microM). This finding suggests that the tetramine disulfide binding site may coincide with that of idazoxan and is different from the NE binding site.

Adrenergic alpha-Antagonists↗
PubMed1986

Hypotensive effect in dogs and rats of intravenous injections of the alpha 1-adrenoreceptor antagonist benoxathian.

The hypotensive effect of the alpha 1-adrenoreceptor antagonist benoxathian has been evaluated in rats and dogs, in comparison to that evoked by WB 4101 and prazosin. In anaesthetized dogs, i.v. injection of benoxathian (25-100 micrograms/kg), WB 4101 (5-25 micrograms/kg) and prazosin (50 micrograms/kg) produced an immediate fall in diastolic blood pressure, which reached a maximum at about 30 sec after drug administration. Whereas the hypotensive effect of prazosin persisted up to 3 hr following injection, the effect of both benoxathian and WB 4101 completely disappeared after 30-60 min. The hypotensive effect of benoxathian was dose-dependent. Pressor responses to i.v. noradrenaline (5 micrograms/kg), adrenaline (5 micrograms/kg) and phenylephrine (20 micrograms/kg) were markedly inhibited (60-75%) by benoxathian (100 micrograms/kg) whilst the pressor response to angiotensin II (0.05 micrograms/kg) was not reduced, but indeed slightly increased. The hypotensive effect of benoxathian (100 micrograms/kg) was abolished following pre-treatment with prazosin (50 micrograms/kg) or hexamethonium (1000 micrograms/kg). In anaesthetized rats similar results were obtained although recovery in blood pressure from the initial drop after i.v. injection of the drugs was slower than in dogs. Benoxathian was slightly more toxic than WB 4101 in rats. In conclusion, present findings show that benoxathian causes a profound hypotensive effect in dogs and in rats through postsynaptic alpha-adrenoreceptor blockade; however its effect, as well as that of WB 4101, is shorter lasting than that of prazosin.

Adrenergic alpha-Antagonists↗
PubMed1985

Structure-activity relationships for prazosin and WB 4101 analogues as alpha 1-adrenoreceptor antagonists.

Several alpha-adrenoreceptor antagonists were prepared by coupling one of the two moieties of WB 4101 (1) with one of the two moieties of prazosin (2). Their blocking activity and relative selectivity on alpha 1- and alpha 2-adrenoreceptors were evaluated in the isolated rat vas deferens. Although retaining a significant selectivity toward alpha 1-adrenoreceptors, all the drugs were weaker antagonists than the parent compounds 1 and 2. Opening the piperazine ring of 2 gave 3, which displayed a very high activity and selectivity toward alpha 1-adrenoreceptors (alpha 1/alpha 2 = 3890). This may have relevance in understanding the mode of action of prazosin. In addition, 3 may represent a valuable tool in the characterization of alpha-adrenoreceptor subtypes.

Adrenergic alpha-Antagonists↗
PubMed1985

Structure-activity relationships among benextramine-related tetraamine disulfides at peripheral alpha-adrenoreceptors.

Several N,N''-(dithiodi-2,1-ethanediyl)bis[N'-(arylmethyl)-1,6-hex anediamines] were prepared and evaluated for their blocking activity on postsynaptic alpha 1-adrenoreceptors in the isolated rat vas deferens. The results were compared with those obtained for benextramine (1). N,N''-(Dithiodi-2,1-ethanediyl)bis[N'-(pyrrol-2-ylmethyl)-1, 6 -hexanediamine] (pyrextramine, 29) was the most potent among the tetraamine disulfides investigated. Thus, it was selected for further pharmacological evaluation to assess its receptor specificity. At a concentration of 10 microM it did not affect the responses elicited by 5-hydroxytryptamine and histamine in guinea pig ileum and by isoproterenol in guinea pig atria and tracheal chain. Furthermore, it was more specific than benextramine (1) toward the muscarinic receptor, being significantly less potent in inhibiting the carbachol-induced response in rat jejunum. These results show that pyrextramine (29) is an irreversible alpha-blocking agent that is more potent and specific than benextramine (1). In conclusion, 29 may be a useful tool in the elucidation and characterization of the peripheral alpha 1-adrenoreceptor.

Animals↗
PubMed1984

N,N''-(dithio-2,1-ethanediyl)bis[N'-(pyrrol-2-ylmethyl)-1, 6,- hexanediamine] (pyrextramine), a new irreversible alpha 1-adrenoreceptor blocking agent of the tetramine disulfide class.

In an attempt to further improve the alpha-adrenoreceptor blocking activity of benextramine, the effect of heteroaromatic substituents on the terminal nitrogens was studied. In this communication we report on the newly synthetized N,N''-(dithio-2,1-ethanediyl)bis[N'-(pyrrol-2-ylmethyl)-1,6- hexanediamine] (pyrextramine) that displayed higher affinity (5-10-fold) and higher selectivity (about 12-fold) than benextramine. These preliminary results show that pyrextramine can replace benextramine in the elucidation and characterization of the peripheral alpha 1-adrenoreceptors.

Adrenergic alpha-Antagonists↗
PubMed1983

The irreversible alpha-blocker benextramine interacts with two different thiol groups.

beta-Haloalkylamines bind at two sites on the adrenergic alpha-receptor, one related to the noradrenaline-recognition site and the other possibly concerned with the calcium channel. In order to verify whether this might apply to other alpha-blockers the tetramine disulfide benextramine was selected owing to its unprecedented covalent selectivity towards the adrenergic alpha-receptor. The fast acting beta-haloalkylamine DMPEA and the "classical" calcium antagonist verapamil were used for protection experiments against benextramine blockade of rat vas deferens adrenergic alpha-receptor. It was demonstrated that two target thiols are probably involved in benextramine binding and one of them might possibly be located at the periphery of, or masked within, the calcium channel which may be connected physiologically to the adrenergic alpha-receptor. However, the hypothesis that the present results could indicate the selective interaction of benextramine with two different subtypes of the adrenergic alpha-receptor is also discussed.

Adrenergic alpha-Antagonists↗
PubMed1982

Inhibition by the tetramine disulphide, benextramine, of cardiac chronotropic histamine H2-receptor-mediated effects.

1 Benextramine (N,N1-bis[o-methoxybenzylamino)-n-hexyl]cystamine), which irreversibly blocks alpha-adrenoceptors and does not inhibit the H1-receptor-mediated contractile effect of histamine on guinea-pig isolated ileum, also did not inhibit the H1-receptor-mediated inotropic effect of histamine on guinea-pig isolated atrium. 2 Benextramine irreversibly inhibited the H2-receptor-mediated chronotropic effect of histamine on guinea-pig isolated atrium. 3 Since its combination with the competitive H2-receptor blocking drug cimetidine had a additive blocking effect, benextramine appears to act directly on the chronotropic H2-receptor.

Adrenergic alpha-Antagonists↗
PubMed1982

Presynaptic effect of clonidine antagonized by the tetramine disulphide, benextramine.

1 The presynaptic alpha-adrenoceptor blocking activity of the newly synthesized alpha-adrenoceptor blocking drug, benextramine, was evaluated in the isolated left atrium of the guinea-pig heart. 2 High-voltage stimulation increased the force of contraction of electrically driven atrial strips, presumably by releasing noradrenaline from sympathetic nerve endings. Like phentolamine, benextramine increased the effect of high-voltage stimulation, presumably by blocking presynaptic alpha-adrenoceptors. 3 Clonidine reduced the effect of high-voltage stimulation, presumably by stimulating presynaptic alpha-adrenoceptors. The inhibitory effect of clonidine was antagonized noncompetitively by benextramine and competitively by phentolamine. 4 Combined administration of benextramine and phentolamine only resulted in the competitive phentolamine antagonism. Thus phentolamine protected the presynaptic alpha-adrenoceptors against benextramine blockade.

Adrenergic alpha-Antagonists↗