Biomedical subjects

A Lapucci

Publications and source records attributed to A Lapucci.

31 records · Page 2Linked to original sources

PubMed1990

Molecular design, synthesis, and antiinflammatory activity of a series of beta-aminoxypropionic acids.

Previous experimental and theoretical studies carried out on the mechanism of action of adrenergic drugs have shown that the (methyleneaminoxy)methyl moiety (C = NOCH2, MAOMM) can be considered as a "bioisostere" of an aryl group (Ar). On this basis, a series of substituted beta-aminoxypropionic acids (AOPAs) were synthesized as analogues of antiinflammatory arylacetic acids (ArAAs), in which the Ar portion is substituted by the MAOMM, with the aim of evaluating whether any antiinflammatory activity could be obtained from this class of drugs after the substitution of the Ar with the MAOMM. The antiinflammatory activity of the AOPAs synthesized was determined by carageenan-induced rat paw edema, using diclofenac as the reference drug. The pharmacological data showed that most of the AOPAs examined exhibit a significant antiinflammatory activity, which in the case of the (E)-3-(benzylideneaminoxy)propionic acid (7q) is very close to that of the reference drug. Structural and theoretical studies were carried out in order to compare the conformation and the molecular reactivity of the AOPAs with those of the ArAAs. Pharmacological results showed that the ArAAs also generally exhibit an antiinflammatory activity after the substitution of the Ar with the MAOMM, thus supporting the hypothesis of a bioisosterelike relationship between these two moieties in this class of NSAIDs.

Alanine↗

PubMed1989

Synthesis and evaluation of the pharmacological activity of rigid analogues of sympathomimetic catecholamines derived from bicyclo[2.2.1]heptane.

endo-3-Amino-exo-2-(3,4-dihydroxyphenyl)-2-hydroxybicyclo[2.2.1]he ptane (4a) and its N-isopropyl derivative (4b) were synthesized and assayed for their adrenergic activity on various isolated preparations. Compounds 4a and 4b, tested up to a dose of 10(-4) M, did not reveal any activity, either stimulant or blocking, on the alpha- and beta-adrenoceptors. Possible rationalizations of the results obtained, however, are suggested.

Animals↗

PubMed1989

Synthesis and antimicrobial properties of substituted beta-aminoxypropionyl penicillins and cephalosporins.

Some beta-aminoxypropionyl penicillins (3) and cephalosporins (4 and 5), planned on the basis of the hypothesis that the (methyleneaminoxy)methyl group (greater than C = NOCH2) could be a "bioisoster" of either aryls or other aromatic groups, were synthesized and assayed for their antimicrobial properties. Compounds 3-5, tested on Gram-positive and Gram-negative bacteria, both sensitive to enzyme inactivation and otherwise, exhibited an activity trend that was not substantially different from that of the corresponding phenylacetamido derivatives taken as terms of comparison.

Ampicillin↗

PubMed1988

An anomalous effect of N-isopropyl substitution in determining beta-adrenergic activity.

We report unexpected results in an investigation of cyclic analogues of dopamine and norepinephrine possessing the structures 1-(aminomethyl)-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (3) and 1-(aminomethyl)-5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthalenol (7). N-Isopropyl substitution of these compounds, providing 4 and 8, brings about the total disappearance of their stimulant activity on beta-adrenergic receptors. On the basis of current knowledge about the structure-activity relationship of adrenergic drugs, it is difficult to provide an explanation for these results; however a tentative rationalization based on conformational considerations is suggested.

1-Propanol↗

PubMed1987

3-[(2-ethoxyphenoxy)methyl]piperidine derivatives. Synthesis and antidepressant activity.

The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.

Animals↗

PubMed1987

Role of the (acyloxy)methyl moiety in eliciting the adrenergic beta-blocking activity of 3-(acyloxy)propanolamines.

Some totally aliphatic 3-(acyloxy)propanolamines were synthesized with the aim of testing whether beta-blocking activity could be obtained from this class of drugs, even in the absence of an aromatic group. The significant and, in most cases, competitive beta-blocking activity shown by the compounds under examination, together with the results of a theoretical study in which their reactivity was compared with that of other adrenergic beta-blocking drugs, seems to confirm a hypothesis previously advanced on the basis of knowledge about the action mechanism of adrenergic beta-blocking drugs and of the results of structural studies. It was also possible to suggest some considerations about the role played by the (acyloxy)methyl portion of 3-(acyloxy)propanolamines in eliciting their adrenergic beta-blocking activity.

Adrenergic beta-Agonists↗

PubMed1986

Conformational effects on the activity of drugs. 11. Stereostructural models for the direct activation of the alpha- and beta-adrenergic receptor.

Two kinds of cyclic analogues of norepinephrine (NE, 7) and isoprenaline (ISO, 8), in which the C(1)-C(2) side chain of these amino alcohols is incorporated in its preferred conformation in the ring of the 2-(3,4-dihydroxyphenyl)-morpholines 9 and 10 (2-DPMs) and in the ring of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 11 and 12 (3-DPPs), respectively, were synthesized and assayed for their adrenergic activity on various isolated preparations. The 2-DPMs and the 3-DPPs showed an alpha- and beta-agonist activity comparable to that of NE and ISO and to that of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 13 and 14 (2-ADTNs), which represent another kind of semirigid analogue of NE and ISO. Through a comparison of the stereo structures of the compounds examined and of their pharmacological properties, it was possible to suggest a spatial situation in which the pharmacophoric groups of the adrenergic drugs examined (aryl moiety, amine nitrogen, and alcoholic or ethereal benzylic oxygen) should interact at the receptor site. This spatial situation corresponds to the one found in the preferred conformation of NE and ISO. It was also possible to construct two theoretical three-dimensional molecular models that provide information about steric requirements for the direct activation of alpha- and beta-adrenoceptors, respectively.

Animals↗

PubMed1985

An interdisciplinary approach to the design of new structures active at the beta-adrenergic receptor. Aliphatic oxime ether derivatives.

On the basis of results previously obtained from structural and theoretical studies on beta-adrenergic drugs, a series of aliphatic oxime ether derivatives (AOEDs) was synthesized. As expected, pharmacological in vitro tests showed that compounds examined exhibit a marked and competitive antagonism at beta-adrenoceptors; the beta 2/beta 1 selectivity ratio indicated that they are more active on the tracheal than on the cardiac beta-receptor. The chemical reactivity of the AOEDs was studied through the calculation of the electrostatic molecular potential (EMP) on a model compound in its preferred conformation. The results showed that the EMP trend agrees with that previously calculated for other beta-blocking drugs.

Adrenergic beta-Antagonists↗

PubMed1983

Conformational effects on the activity of drugs. 10. Synthesis, conformation, and pharmacological properties of 1-(2,5-dimethoxyphenyl)-2-aminoethanols and their morpholine analogues.

In order to obtain a better understanding of the effects that structural parameters have on the changes of adrenergic activity when 1-aryl-2-aminoethanol derivatives are converted into their corresponding 2-arylmorpholine cyclic analogues, we synthesized 1-(2,5-dimethoxyphenyl)-2-aminoethanol derivatives 5-7 and their morpholine analogues 8-10. The preferred conformation of amino alcohols and their cyclic analogues have been determined through an H NMR and IR study. Compounds 5 and 6 showed both alpha-stimulating and alpha-blocking activity on rat vas deferens, the effect depending on the concentration employed; on the same isolated tissue, N-isopropyl derivative 7 and the morpholine analogues 8-10 exhibited only alpha-blocking activity. As for the beta-adrenergic activity, only the open-chain compound 7 possessed a moderate blocking effect on isolated guinea pig atria. The results of this work seem to indicate that the changes of pharmacological activity involved in the transformation of the adrenergic drugs into their morpholine analogues are influenced more by characteristic features of the aromatic moiety than by the ethanolamine or propanolamine structure of the drugs.

Animals↗

PubMed1981

Structure--activity relationship in cinnamamides. 3. Synthesis and anticonvulsant activity evaluation of some derivatives of (E)- and (Z)-m-(trifluoromethyl)cinnamamide.

The (E)- and (Z)-m-(trifluoromethyl)-alpha, beta-dimethylcinnamamides and some of their N-alkyl derivatives were prepared and pharmacologically tested as anticonvulsant agents in order to verify if a ring substituent, like the m-CF3 group, different from a halogen but possessing the same electronic effect could lead to equally active compounds. Some (E)-m-(trifluoromethyl)-alpha-methyl- and -non-methyl-substituted-cinnamamides were also prepared and tested. In the alpha, beta-dimethyl series the results show that the m-CF3 group leads to products more active than the ones unsubstituted on the phenyl ring but still less active than the p-halogen-substituted compounds previously studied. In the alpha-methyl and non-methyl-substituted series, the trend shows the m-CF3 group being able to produce less toxic and, in some cases, more active products than the previously studied amides.

Animals↗

PubMed1979

Conformational effects on the activity of drugs. 7. Synthesis and pharmacological properties of 2-(p-nitrophenyl)-substituted morpholines.

A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adrenergic-stimulating activity and the potentiating effect on the responses to norepinephrine found in the open-chain compounds persist in their corresponding semirigid cyclic analogues. The results are discussed in the light of common knowledge of the structure-activity relationships of alpha-adrenergic drugs.

Adrenergic alpha-Antagonists↗

PubMedDate not supplied

Prevention of corneal keratocyte apoptosis after argon fluoride excimer laser irradiation with the free radical scavenger ubiquinone Q10.

PURPOSE: To assess in vitro the potential of the free radical scavenger ubiquinone Q10 in preventing keratocyte apoptosis after argon fluoride (ArF) excimer laser irradiation. METHODS: Cultured rabbit keratocytes were irradiated at very low single-pulse laser fluences. The cumulative effects generated by three total fluence doses between 12 and 45 mJ/cm2, representative of single-pulse subablative doses during photorefractive keratectomy (PRK) in humans, were evaluated. We employed the following parameters to compare pretreated (10 microM ubiquinone Q10) and untreated samples: 1) number and morphology of living cells by Trypan blue test and ultramicroscopy, respectively; 2) level of free-radical formation assessed by malonaldehyde quantitation; 3) cellular energy level evaluated by ATP assay. RESULTS: Excimer laser irradiation kills cultured keratocytes by inducing apoptosis. The effect increases with the cumulative fluence dose. In the samples pretreated with ubiquinone Q10 there were significantly fewer cumulative apoptotic events than in the untreated ones. Quantitative analysis of malonaldehyde cellular levels suggested this protective action of ubiquinone Q10 was connected with its ability to scavenge laser-generated free radicals. ATP assay also confirmed that it raised cellular energy levels. CONCLUSIONS: The treatment of corneal keratocytes with relatively low concentrations of ubiquinone Q10 can prevent apoptosis after ArF excimer laser irradiation. If these findings are confirmed on human keratocytes this treatment could be usefully exploited in the PRK surgical procedure. That might lead to a reduction in the occurrence of haze and curvature regression triggered by programmed cell death.

Adenosine Triphosphate↗

PubMedDate not supplied

Synthesis and beta-adrenergic activity of a series of 3-(substituted-benzylideneaminoxy)propanolamine derivatives.

In an attempt to change the beta-adrenergic properties of completely aliphatic 3-(methyleneaminoxy)propanolamine derivatives, from antagonist to agonist, while still retaining the beta 2-selectivity, we described, in a previous paper, the synthesis of a series of such derivatives possessing a hydroxy or methoxy group linked to the aliphatic substituent present on the oximic carbon. However, pharmacological tests indicated that these compounds maintain the competitive antagonism on beta receptors. In this paper, the synthesis and the results of functional tests on isolated preparations are reported for a new series of 3-(substituted-benzylideneaminoxy)propanolamine derivatives in which either the hydroxy or the methoxy group is linked to a phenyl ring present on the oximic carbon. The results obtained are then discussed, taking into account the conformational and reactivity properties of these compounds, determined by means of theoretical calculations.

Adrenergic beta-1 Receptor Agonists↗