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C Melchiorre

Publications and source records attributed to C Melchiorre.

At least 91 records · Page 5Linked to original sources
PubMed1982

Inhibition of adrenaline-induced platelet aggregation by the alpha-adrenoceptor blocking drug benextramine.

1 The activity of the irreversible alpha-adrenoceptor blocking drug, benextramine, was determined in human platelets. 2 Compared to its postsynaptic and presynaptic alpha-adrenoceptor blocking potency, benextramine had a very low potency as an antagonist of adrenaline-induced platelet aggregation. 3 The results confirm the previous observation with the irreversible alpha-adrenoceptor blocking drug, phenoxybenzamine, that platelet alpha-adrenoceptors differ from postsynaptic and presynaptic alpha-adrenoceptors.

Adenosine Diphosphate↗
PubMed1981

Molecular requirements of the active site of cholinergic receptors XV: Synthesis and biological activity of 2,3-dehydrodeoxamuscarone and 2,3-dehydrodeoxamuscarines.

To elucidate the molecular requirements of the active sites of cholinergic receptors, 3-methyl-4-oxo-1-(N,N-dimethylaminomethyl)cyclopent-2-ene methiodide (2,3-dehydrodeoxamuscarone) and cis- and trans-3-methyl-4-hydroxy-1-(N,N-dimethylaminomethyl)cyclopent-2-ene methiodides (cis- and trans-dehydrodeoxamuscarines) were synthesized and tested. The results, compared with those of the corresponding oxygenated compounds, seem to indicate the 2,3-dehydrodeoxamuscarines and muscarine bind at the same site while 2,3-dehydrodeoxamuscarone interacts with the site normally occupied by muscarone. Furthermore, the previously suggested hypothesis that the unpolar site might somehow incorporate that of muscarone was considered.

Animals↗
PubMed1980

Potentiation and inhibition of nicotinic effects on striated muscle by the tetramine disulfide benextramine.

In low concentrations (0.3-3 muM) the tetramine disulfide benextramine (BHC; N,N'-bis[6-(o-methoxybenzylamino)-n-hexyl]cystamine) potentiated the contracture of the isolated frog rectus abdominis muscle caused by acetylcholine but in the presence of physostigmine or in a higher concentration (10 muM) it inhibited. Benextramine only inhibited the contracture caused by carbachol or butyrylcholine. The all-carbon analog of benextramine only inhibited the effect of acetylcholine. The inhibitory effects of benextramine and its carbon analog were noncompetitive and readily reversible but the potentiating effect of benextramine was not readily reversible.

Acetylcholine↗
PubMed1980

Irreversible alpha adrenoceptor blocking effects and reversible muscarinic blocking and nicotinic blocking effects of tetramine disulfides on the heart.

Inotropic effects of phenylephrine, carbachol, and butyrylcholine were used in the rabbit left atrium to evaluate respectively alpha adrenoceptor blocking, muscarinic blocking, and nicotinic blocking effects of tetramine disulfides ((RNH(CH2)nNH(CH2)2S-)2 x 4HX). The alpha adrenoceptor blocking potencies of newly synthesized derivatives R = 3',4'-(OH)2-benzyl, n = 5-9, were similar to those of compounds R = 2'-OCH2-benzyl, n = 5-7. Muscarinic blocking and nicotinic blocking potencies of tetramine disulfides were correlated with alpha adrenoceptor blocking potency. Compounds R = 3',4'-(OH)2-benzyl had relatively low muscarinic blocking potencies and compounds R = 2'-OCH3-benzyl had relatively low nicotinic blocking potencies.

Adrenergic alpha-Antagonists↗
PubMed1980

Reactivation by cysteamine of vascular alpha adrenoceptors blocked by the tetramine disulfide benextramine and interaction of benextramine with phenoxybenzamine.

The tetramine disulfide benextramine irreversibly blocked the noradrenaline-induced contraction of the isolated rabbit aorta in a manner similar to that observed with phenoxybenzamine. Cysteamine abolished the benextramine blockade but not the phenoxybenzamine blockade. Incubation of aortic tissue with benextramine prior to phenoxybenzamine exposure and followed by cysteamine treatment led to a recovery of the noradrenaline response that depended on the dose of benextramine. Thus benextramine protected the alpha adrenoceptors against phenoxybenzamine blockade.

Animals↗
PubMed1980

Selectivity of alpha 1 and alpha 2 adrenergic agonists and antagonists.

The recent contributions in the selectivity of ligands acting at the adrenergic alpha-receptor toward pre- and post-synaptic receptors (i.e. alpha 1 and alpha 2-receptors) are reviewed. Furthermore, tissue differences and possible sub-classification of pre- and post-synaptic alpha-receptor types are discussed.

Adrenergic alpha-Agonists↗
PubMed1980

Molecular requirements of the active sites of the cholinergic receptors. XII - 3-Methyl-2-oxo-1-dimethylaminomethylcyclopentane methiodide as a new selective agonist for the nicotinic receptor.

To investigate further the nature of the active sites of cholinergic receptors, the carbocyclic analogs of isomuscarone and isomuscarine [(IV) and (V a-d)] were synthesized and tested for their cholinergic activity. Like isomuscarines, such compounds are completely devoid of muscarinic activity which further support the hypothesis that the receptor site, corresponding to position 2 of the ring, cannot accept groups larger than and/or with a dipole having a different direction from that of an ether oxygen. On the other hand nicotinic activity is quite good. In this respect compound (IV) is particulary interesting, being as active as ACh and pratically devoid of muscarinic activity.

Abdominal Muscles↗
PubMed1979

Cardiac muscarinic blocking and atropinic blocking effects of a tetramine disulfide and alpha-adrenoceptor blocking activity.

Since many alpha-adrenoceptor blocking drugs were known to have muscarinic blocking activity, BHC, a newly synthesized tetramine disulfide with alpha-adrenoceptor blocking activity, and two of its analogs were tested for muscarinic blocking activity in the isolated guinea pig atrium and ileum. BHC had muscarinic blocking activity. Its potency was higher in the atrium than in the ileum. The cardiac muscarinic blocking potency of the analog that contained carbon atoms instead of sulfur atoms was similar to that of BHC. Lower concentrations of the drugs antagonized inotropic effects of acetylcholine competitively, but higher concentrations had a smaller effect than expected for competitive antagonism. In the atrium BHC competitively inhibited the muscarinic blocking effect of atropine. Its atropinic blocking potency was similar to the muscarinic blocking potency. Quinidine and gallamine also had muscarinic blocking and atropinic blocking effects in the atrium but were about 10 times less potent than BHC.

Adrenergic alpha-Antagonists↗
PubMed1979

Inhibition of the cardiac inotropic effect of phenylephrine by a tetramine disulfide with irreversible alpha-adrenoceptor blocking activity.

The newly synthesized alpha-adrenoceptor blocking drug BHC (N,N'-bis[6-(10-methoxybenzyl-amino)-a-hexyl]cystamine) was found to block irreversibly the positive inotropic effect of the sympathomimetic drug phenylephrine on the isolated rat left atrium. BHC was used to test the adrenoceptor interconversion hypothesis which claims that low temperature converts inotropic beta-adrenoceptors in rat atrium and frog ventricle to alpha-adrenoceptors. There was no evidence of adrenoceptor 'interconversion.' In the rat atrium low temperature did not increase the BHC antagonism of phenylephrine and did not cause BHC to inhibit the inotropic effect of noradrenaline or isoprenaline. In the perfused frog heart low temperature did not lead BHC to inhibit the inotropic effect of phenylephrine, adrenaline, or isoprenaline.

Adrenergic alpha-Antagonists↗
PubMed1978

Molecular properties of the adrenergic alpha-receptor. III - Origin of topographical dualism in the reaction of a receptor thiol with symmetrical and unsymmetrical polyamine disulfides.

Structure activity relationship studies previously led to the discovery of two distinct classes of tetramine-disulfides [(I) and (II)] each exhibiting optimum adrenergic alpha-blocking activity. The more potent one (I) was shown to uniquely discriminate between noradrenaline (NA) and adrenaline (A) binding sites. The unusual receptor topographical dualism toward (I) and (II) led to an investigation of the role of structural symmetry in their interaction with the receptor. To this end, a series of unsymmetrical disulfide analogs (x-z) where half of (I) was retained and the other half was made of unsubstituted N-(omega-aminoalkyl)cysteamines [as present in (II) and its homologs] were synthesized and evaluated as alpha-blockers. In addition, the role of the number of basic nitrogens on activity was also examined. It was found that the presence of four nitrogens is necessary for optimum activity. Moreover, it was discovered that optimum alpha-blocking potency is obtained when the respective halves of the two best prototypes (I) and (II) of symmetrical structures are fused [compound (XVI)]. This new unsymmetrical tetramine disulfide has a potency approaching that of (I) and its receptor saturation mechanism is similar. Moreover, it also shares with (I) the ability to discriminate between NA and A elicited responses. The effect of methylation of a single inner nitrogen on potency allowed the conclusion that each half of the unsymmetrical disulfide (XVI) respectively occupy half of the sites for (I) and half of those for (II). Accordingly, the previously observed topographical dualism toward (I) and (II) can best be accommodated by a model where two distinct sets of sites crossing each other over the same receptor thiol are involved. The possible significance of the anionic site multiplicity of the alpha-receptor is briefly discussed.

Adrenergic alpha-Antagonists↗
PubMed1978

Molecular properties of the adrenergic alpha-receptor. I--Structural requirements for specific covalent occupancy by N,N'-bis--(5-aminopentyl)cystamine derivatives.

The synthesis and alpha-adrenoreceptor blocking activity of several substituted analogs of the prototype alpha-blocker N,N'-bis-(5-aminopentyl)cystamine (APC) are described. The three optical forms of the analog carrying methyl groups on the carbons alpha- to the sulfurs were synthesized and shown to be equipotent and somewhat less active than APC. The omega, omega'-bis-guanidino analog of APC was less active. Significant improvement in potency was observed only with APC analogs carrying benzyl and substituted benzyl groups on the terminal nitrogens. Linking the terminal nitrogens of APC with a p.xyledenyl group so as to give the 26-membered analog caused a sharp drop in activity. The significance of these results as regards the alpha-receptor topography is discussed.

Adrenergic alpha-Antagonists↗
PubMed1976

Cholinergic compounds VII - Synthesis and pharmacological activity of some trimethylammonium iodides related to desethermuscarine.

Some substances similar to desethermuscarine were synthesized and studied as cholinergics on isolated organs. The results show the importance of the cyclopentane nucleus with regard to activity. The activity of 3-methyltrimethylammonium hexane iodide is particularly interesting for, though lacking the oxygenated function in 3 and having a different methyl spatial arrangement, this compound is only ten times less active than desethermuscarone.

Animals↗
PubMed1975

Cholinergic compounds. II - Synthesis and biological activity of epi- and allo-desethermuscarines.

To obtain further clarification of structure-activity relationships of cholinergic substances, which would give better understanding of cholinergic receptors, the carbocyclic analogs of epi-muscarine (I) and allo-muscarine (II) were prepared starting from 6-methyl-3-oxo-2-oxabicyclo[2.2.1]heptane (IV). Pharmacological tests show that these two compounds possess lower muscarinic activity than the carbocyclic analog of muscarine (desethermuscarine), the allo isomer being from 5 to 500 times more active than the epi isomer. Therefore, the activity in the carbocyclic series follows, for these receptors, the same pattern as the oxygenated one. As far as nicotinic activity is concerned. (I) is 2.5 times more active than (II), the effective doses being from 40 to 100 times higher than that of Ach. These results suggest a steric rather than an electronic influence for the ether oxygen, whose principal role seems to be that of contributing to the rigidity of the molecule. For most receptors assayed, an inverse relationship between the potency ratio of the isomers and the sensitivity towards Ach has been observed.

Animals↗