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Biomedical subjects

F Gualtieri

Publications and source records attributed to F Gualtieri.

At least 55 records · Page 3Linked to original sources
PubMed1994

Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 2. 2-Phenoxy-, 2-(phenylthio)-, and 2-(phenylamino)alkanoic acid esters.

Further modifications of the leads ((R)-(+)-hyoscyamine and (p-chlorophenyl)propionic acid alpha-tropanyl ester), which show analgesic and nootropic activities as a consequence of increased central presynaptic ACh release, are reported. 2-Phenoxy- and 2-(phenylthio)alkanoic acid esters showed the best results. Several members of these classes possess analgesic properties which are comparable to that of morphine and at the same time are able to reverse dicyclomine-induced amnesia. Confirmation was found that the mechanism of action is due to an increase in ACh release at central muscarinic synapses and that both auto- and heteroreceptors controlling ACh release are very likely involved. According to the results obtained with (R)-(+)-hyoscyamine, analgesic activity is stereochemistry dependent, since the R-(+)-enantiomers are always more efficacious than the corresponding S-(-)-ones. On the basis of their potency and acute toxicity, compounds (+/-)-28 (SM21) and (+/-)-42 (SM32) were selected for further study.

Acetates↗
PubMed1994

Semi-rigid analogues of the calcium antagonist verapamil: a molecular modelling study.

In this work the rigid-analogue approach has been used to obtain information on the active conformation(s) of the calcium antagonist verapamil. A series of semi-rigid analogues of verapamil were synthesized and their biological activities evaluated on guinea-pig heart and aorta. These molecules were analysed by means of molecular modelling techniques. On the basis of the pharmacological profile and conformational analysis of these compounds, two different models for negative inotropic and negative chronotropic activity are proposed. The two actions seem to be due to conformations of the molecules which differ in the orientation of their phenylethylamino groups.

Animals↗
PubMed1994

Dialkylaminoalkyl esters of 2,2-diphenyl-2-alkylthioacetic acids: a new class of potent and functionally selective muscarinic antagonists.

The synthesis and pharmacological activity as muscarinic antagonists of a number of 2-alkylthio-2,2-diphenylacetic acid esters are reported. The compounds studied are potent muscarinic antagonists and many of them show from moderate to high selectivity toward M2 or toward M1 and M2 receptors when tested on tissues but lack selectivity on five muscarinic human receptors (m1-m5) cloned and expressed in CHO-K1 cells. As a consequence, the compounds behave as functionally selective antagonists. Those showing M2 selectivity appear to be good drug candidates for the treatment of cognitive disorders connected with central cholinergic deficit.

Animals↗
PubMed1994

1,3-oxathiolane muscarinic ligands modified at the cationic head.

In order to develop compounds which may be useful in the treatment of memory and cognitive disorders we have synthesized and tested some 1,3-oxathiolane derivatives bearing an amidine function instead of the classical ammonium head, with the aim of improving brain penetration. The compounds were tested on peripheral and central models of muscarinic receptors. The results show that, unlike for other series of muscarinic ligands, this modification results in the reduced potency of antagonists, shifts the activity of agonists toward weak antagonism and does not introduce any noteworthy subtype selectivity.

Amidines↗
PubMed1993

Verapamil analogues with restricted molecular flexibility: synthesis and pharmacological evaluation of the four isomers of alpha-[1-[3-[N-[1- [2-(3,4-dimethoxyphenyl)ethyl]]-N-methylamino]cyclohexyl]]-alpha- isopropyl-3,4-dimethoxybenzene-acetonitrile.

The synthesis and pharmacological activities of the four isomeric racemates of alpha-[1-[3-[N-[1-[2-(3,4-dimethoxyphenyl)ethyl]]-N- methylamino]cyclohexyl]]-alpha-isopropyl-3,4-dimethoxybenzene-acetoni trile are reported (2a-d). The compounds are verapamil analogues with restricted molecular flexibility designed to gather information on the active conformation(s) of the parent drug. The relative stereochemistry of the four racemates was established by X-ray crystallography and by 1H NMR spectroscopy; conformational analysis was supported by theoretical calculations. Negative inotropic and chronotropic activities were evaluated on guinea pig atria, while vasodilatory activity on smooth muscle was tested on guinea pig aortic strips. Binding studies on cat ventricles were performed using (-)-[N-methyl-3H]desmethoxyverapamil (D888) as a reference ligand. The results seem to support the hypothesis that cardiac depressant and vasorelaxant activities are due to different conformations of the verapamil molecule.

Acetonitriles↗
PubMed1991

Verapamil analogues with restricted molecular flexibility.

Three analogues with restricted flexibility were designed to study the active conformation of verapamil during interaction with the slow calcium channel. Thus cis- and trans-1-(3,4-dimethoxyphenyl)-4-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N- methylamino]-r-1-cyclohexanecarbonitrile (5a and 5b), and 4-(3,4-dimethoxyphenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-cyanopiper idine, in which the verapamil structure is inserted into a cyclohexane or piperidine ring, were synthesized. Conformational analysis was performed with NMR and theoretical methods, and slow calcium channel antagonism was tested on guinea pig aorta strips. The compounds are some 100 times less potent than the parent compound even if they are able to reach conformations that are quite close to the lowest energy conformation proposed for verapamil and similar compounds. It appears that the flexibility to rotate around the bond between the quaternary atom and the adjacent methylene, a property which is lost in compounds 5a, 5b, and 6, is a major requisite for the calcium antagonism of verapamil.

Animals↗
PubMed1990

Eudismic analysis of a series of muscarinic ligands carrying a 1,3-oxathiolane nucleus.

Eudismic analysis was performed on a set of 14 muscarinic ligands carrying a 1,3-oxathiolane nucleus, in order to obtain information about both the existence of receptor subgroups and of agonist and competitive antagonist interaction sites. The results obtained were compared with those from a study of the enantioselectivity of the pairs of enantiomers. The two approaches do not appear to be completely equivalent and would seem to complement each other usefully.

Animals↗
PubMed1989

A search for calcium-channel activators in the verapamil series.

A new series of phenylalkylamines related to Verapamil have been synthesized and their Ca2+-modulating activity on rabbit aorta and on guinea-pig heart were evaluated. The compounds display only a moderate Ca2+-antagonistic activity; none of them showed any Ca2+-agonistic effect.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane 3-oxide methiodides.

The eight isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1, 3-oxathiolane 3-oxide methiodides were prepared and their absolute configurations were attributed by synthesis and by X-ray crystallography. The compounds were tested on guinea pig bladder, ileum, and heart and their antimuscarinic potency was evaluated and expressed as pA2. The absolute configuration of the most potent isomer [(+)-(2R,3R,5R)-7] is identical with that of the corresponding agonist [(2R,3R,5R)-c-2-methyl-r-5-[(dimethylamino)methyl]-1,3-oxathiolane t-e-oxide methiodide],3 which further supports our previous hypothesis that muscarinic agonists and antagonists of this series recognize a common binding site. While some of the racemates (3,4) show different enantioselectivity on the different tissues, the most potent and the most enantioselective one (7) does not discriminate between muscarinic receptors as it shows eudismic ratios of the same order for all tissues examined.

Animals↗
PubMed1989

Negative inotropic and calcium antagonistic activity of alkyl and arylalkyl phosphonates.

Several alkyl and arylalkyl diethylphosphonates related to fostedil have been synthetized and tested for negative inotropic activity (isolated guinea pig left atrium) and Ca++ antagonistic activity (isolated guinea pig aortic strips). The results show that negative inotropic and Ca++ antagonistic activity might depend from different molecular features.

Animals↗
PubMed1989

On the site of interaction of some muscarinic agonists and competitive antagonists.

The stereochemistry of interaction of several 1,3-oxathiolane muscarinic ligands is considered and discussed. On the basis of the identical absolute configuration of the most affinitive enantiomers of agonists and antagonists it is suggested that the two kinds of ligands interact with an identical binding site, namely the recognition site of Acetylcholine. The hypothesis is extended to other muscarinic antagonists like the bulky esters of choline, 2,2-disubstituted-1,3-dioxolanes and Atropine-like compounds; a model for such an interaction is proposed.

Animals↗
PubMed1988

Chiral muscarinic agonists possessing a 1,3-oxathiolane nucleus: enantio- and tissue-selectivity on isolated preparations of guinea-pig ileum and atria and of rat urinary bladder.

Racemate and corresponding enantiomers of muscarinic agonists carrying a 1,3-oxathiolane nucleus were studied on isolated preparations of guinea-pig ileum and atria and of rat urinary bladder. The efficacy of these agonists were determined according to the method of Furchgott and Bursztyn (1967) and enantio-selectivity and tissue-selectivity were investigated. The enantio-selectivities of the most potent compounds studied (expressed as the ratio of potencies or affinities of the enantiomers) vary significantly from tissue to tissue, supporting the view that M2 receptors are not homogeneous. In particular, the data all indicate that the ileal receptors are different to the atrial and bladder ones.

Animals↗
PubMed1988

Enantioselectivity of muscarinic antagonists. 2,2-Dicyclohexyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides and related 3-oxides.

The enantiomers of three chiral muscarinic antagonists carrying a 1,3-oxathiolane nucleus were prepared and their absolute configuration established. The enantioselectivity and tissue selectivity of such compounds were studied on rat bladder and guinea pig ileum and heart. The results show that introduction of a sulfoxide function brings about a small but definite enantioselectivity in the 1,3-oxathiolane compound (2), which in itself does not show enantioselectivity among the tissues studied. The results obtained point to differences among cardiac and ileal muscarinic receptors. Comparison of the absolute configuration related agonists shows that the most potent isomers of both series share the same absolute stereochemistry.

Animals↗
PubMed1988

Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides.

The four isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl] -1,3-oxathiolane methiodide were prepared. Their absolute configuration was attributed by means of X-ray crystallography and circular dichroism. The compounds were tested on rat bladder and guinea pig ileum and heart, and their antimuscarinic potency was evaluated and expressed as pA2. The results show that the introduction of a chiral center into position 2 brings about a small but definite enantioselectivity on rat bladder and guinea pig ileum which is not seen for guinea pig heart. This supports the view that differences exist among the muscarinic receptors of these tissues (M2 receptors). Comparison of the absolute configuration of the antagonists studied in this and in the preceding paper2 and that of strictly related agonists supports the hypothesis of a common binding site for agonists and antagonists of this kind.

Animals↗
PubMed1987

Resolution, absolute configuration, and cholinergic enantioselectivity of (-)- and (+)-c-2-methyl-r-5-[(dimethylamino)methyl]-1,3-oxathiolane t-3-oxide methiodide and related sulfones.

As a continuation of previous studies on chiral cholinergic agonists carrying a 1,3-oxathiolane nucleus, the enantiomers of c-2-methyl-r-5-[(dimethylamino)methyl]-1,3-oxathiolane t-3-oxide methiodide ((+)- and (-)-1) and of cis-2-methyl-5-[(dimethylamino)methyl]-1,3-oxathiolane 3,3-dioxide ((+)- and (-)-2) were obtained and their absolute configurations established by synthesis. The cholinergic potency of the four isomers was evaluated in vitro on guinea pig ileum and frog rectus abdominis models, and the results show that (-)-1, which has the same absolute configuration as L-(+)-muscarine, is a selective and potent muscarinic agent. The (+)-1 enantiomer is some hundred times less potent than (-)-1 on the muscarinic guinea pig ileum while, on the same tissue, the corresponding sulfone derivatives ((+)- and (-)-2) show no enantioselectivity.

Animals↗