New N-n-propyl-substituted 3-aryl- and 3-cyclohexylpiperidines as partial agonists at the D4 dopamine receptor.

We have previously reported that compounds dimethyl-substituted on the phenyl ring of N-n-propyl-3-phenylpiperidines (PPEs) have a high (nM) affinity and selectivity toward the D(4) dopamine receptor (D(4) DAR) with m,p-dimethyl PPE (1) having the highest affinity and selectivity. In the present paper we have investigated the role of the methyl substitution by the synthesis of monomethylated (2a-c) and nonmethylated (2d) PPEs followed by the characterization of their biological properties using receptor binding assays. Our findings reveal that the methyl substitution of the phenyl ring is not necessary for a high and selective binding affinity to the D(4) DAR.

Synthesis, antifungal activity, and molecular modeling studies of new inverted oxime ethers of oxiconazole.

Some new oxime ethers of types 7 and 8, in which the methyleneaminoxy group, C=N-O, of oxiconazole 6 is in an inverted atomic sequence, were synthesized and tested for their antifungal activities. Among them, the type 7 compounds, such as the N-ethoxy-morpholino-substituted derivatives 7l-o (Table 1), showed good antifungal properties against the Candida strains tested, with minimum inhibitory concentration (MIC) values similar to those of the reference drug 6. A remarkable result was obtained with these types of azoles, which had shown a cidal character against Candida albicans, while the reference drug oxiconazole was only fungistatic in the same tests.

(E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](arylmethyloxy)amines. Methyleneaminoxymethyl (MAOM) analogues of diarylcyclopentenyl cyclooxygenase-2 inhibitors: synthesis and biological properties.

The (E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](methyloxy)amine (5) and (arylmethyloxy)amines (6-12) were designed in order to verify the effects on the biological properties of the substitution of an aryl of selective diarylcyclopentenyl cyclooxygenase-2 (COX-2) inhibitors of type 3 with a methyleneaminoxymethyl moiety (MAOMM). Compounds 5-12 were tested in vitro for their inhibitory activity towards COX-1 and COX-2 by measuring prostaglandin E2 (PGE2) production in U937 cell lines and activated J774.2 macrophages, respectively.

Spirotetrahydronaphthalene analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidines].

The 5,6- (5a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidine] (6a) and their N-isopropyl derivatives (5b and 6b), DDSNPs, were synthesized. These compounds can be viewed as the result of the combination of the structure of the 3-(3,4-dihydroxyphenyl)-piperidine 2a or 2b, with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy-(3a or 3b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (4a or 4b), 1-AMDTNs. The new compounds (5a, b and 6a, b) were assayed for their alpha and beta adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described 3-(3,4-dihydroxyphenyl)piperidine (3-DPP; 2) and 1-AMDTNs (3, 4).

Synthesis and dopaminergic properties of the two enantiomers of 3-(3,4-dimethylphenyl)-1-propylpiperidine, a potent and selective dopamine D4 receptor ligand.

The synthesis of the two enantiomers of 3-(3,4-dimethylphenyl)-1-propylpiperidine 1, a potent and selective D4 dopaminergic ligand, was performed. The 3-(3,4-dimethylphenyl)- 1-propylpiperidine with the R configuration showed an affinity for the D4 receptors 6-fold higher than the corresponding enantiomer with the S configuration. Furthermore, the (R)-1 enantiomer proved to be highly selective for D4 receptors with respect to D2-D3 receptors, with a Ki ratio higher than 25,000, while the (S)-1 enantiomer was about 100-fold less selective than the (R)-1 one.

Synthesis, inhibitory activity towards human leukocyte elastase and molecular modelling studies of 1-carbamoyl-4-methyleneaminoxyazetidinones.

Some monocyclic beta-lactam derivatives of type 3 (MAOAs) in which the leaving group (LG) on the C(4) is a methyleneaminoxy moiety, were synthesised and tested in vitro and in vivo for their inhibitory activity towards human leukocyte elastase (HLE). Some compounds showed an appreciable in vitro inhibitory activity against this enzyme. Effects on the anti-HLE activity due to the nature of the substituents R and R(1) present on their LG were observed and rationalised by means of molecular modelling techniques.

N-n-Propyl-substituted 3-(dimethylphenyl)piperidines display novel discriminative properties between dopamine receptor subtypes: synthesis and receptor binding studies.

3-Phenylpiperidines (PPEs) have been thoroughly investigated in view of their interesting dopaminergic activity, and the N-n-propyl substitution has been suggested as the most effective among several PPEs differently substituted on the phenyl ring. In previous studies, we found that the dimethyl substitution on the phenyl ring of N-unsubstituted PPEs provided compounds active toward alpha2-adrenergic receptors (alpha2-ARs), which proved to possess interesting selectivity properties. The high degree of homology between the binding domains of alpha2-ARs and D4-dopaminergic receptors (D4-DARs) prompted us to verify whether this kind of substitution on the aromatic ring might prove to be active against retinal DARs of the D4 subtype.

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.

Synthesis and adrenergic beta-blocking activity of ortho-, meta- and para-oxypropanolamino-substituted [(benzylideneamino)oxy]propanolamines.

The N-isopropyl- and N-t-butyl-substituted 1-[o-(3-amino-2-hydroxypropoxy)benzylideneaminoxy]-3-amino-2-propa nols (7a,b) and their meta (8a,b) and para (9a,b) isomers, in which a single aromatic ring is substituted both by the oxypropanolaminic chain of (aryloxy)propanolaminic beta-adrenergic antagonists (AOPAs) and the [(methyleneamino)oxy]propanolaminic chain of [(methyleneamino)oxy]-propanolaminic beta-blocking drugs (MAOPAs), were synthesized and assayed for their beta-adrenergic activity by functional tests on isolated preparations. Compounds 7-9 represent a new type of molecular duplication of beta-adrenergic drugs, formally deriving from the sharing of the aromatic portions of two different pharmacophoric subunits, namely the (aryloxy)propanolaminic portion of AOPAs and the [(benzylideneamino)oxy]propanolaminic portion of aryl-substituted MAOPAs. The pharmacological results showed that the beta-blocking activity of compounds 7-9 is closely related to the way in which the two subunits are linked by the aromatic nucleus: the activity decreases on passing from the ortho-compounds (7a,b) to the meta (8a,b) and then to the para (9a,b) isomers.

Synthesis, antiinflammatory activity and platelet antiaggregating activity of a new series of beta-aminoxypropionic acids.

A series of beta-aminoxypropionic acids (AOPAs) had previously been designed and synthesised as analogues of antiinflammatory arylacetic acids (ArAAs) in which the Ar portion is substituted by the (methyleneaminoxy) methyl moiety (C = NOCH2, MAOMM). Most of these AOPAs had exhibited a significant antiinflammatory and antiaggregating activity. This paper reports the synthesis of a new series of beta-aminoxypropionic acids (SAOPAs) which include the saturated (methylaminoxy)methyl moiety (CHNH-OCH2, SMAOMM) in the place of the MAOMM present in AOPAs.

The [(methyloxy)imino]methyl moiety as a bioisoster of aryl. A novel class of completely aliphatic beta-adrenergic receptor antagonists.

Previous studies in the field of beta-adrenergic drugs had supported the hypothesis of the existence of a bioisosterism between the [(methyleneamino)oxy]methyl moiety (C = NOCH2, MAOMM) of type B beta-blocking drugs and the aryl (Ar) of type A beta-blocking agents. In the MAOMM, however, the carbon of the CH2 linked to the oximic oxygen possesses a hybridization (sp3) and a geometry different from those of the corresponding carbon of Ar which possesses an sp2 hybridization. Furthermore, in the MAOMM, in its preferred conformation, the unsaturated portion (C = N) is situated in a spatial area which does not correspond exactly to the area occupied by Ar.

Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.

In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO).

Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.

The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists.

Synthesis and antimicrobial properties of substituted 3-aminoxypropionyl and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams.

The substituted 3-aminoxyproprionyl (VII) and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams (VIII) which possess the monocyclic beta-lactam nucleus of aztreonam (IX) were synthesized by reaction of triethylammonium (3S, 4S)-3-amino-4-methyl-2-oxo-1-azetidinsulfonate with the aminoxy acids X and XI, respectively. Compounds VII and VIII were assayed in vitro for their antimicrobial properties against Gram-positive and Gram-negative bacteria, whether producers of beta-lactamases or otherwise. Both types of compounds (VII and VIII) exhibited a poor antibacterial activity towards Gram-positive bacteria, comparable to that of aztreonam.

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.

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.

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.

Molecular orbital studies on the mechanism of drug-receptor interaction. 5. Molecular reactivity and receptor affinity of beta-agonist adrenergic drugs.

The electrostatic molecular potential (EMP) of model compounds (isoproterenol and four of its analogs) with agonist activity on the beta-adrenergic receptor was investigated, at the SCF-MO ab initio level. A method was developed to calculate the drug-receptor interaction energy (delta E) for these compounds, and the EMP and delta E values were compared with the affinity of the drugs for the beta-adrenergic receptor, quantified in terms of pKd. Our results indicate that the aromatic ring takes part in its entirely in the interaction with the receptor.

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.

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.

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.

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.

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.

Synthesis and antibacterial activities of new (alpha-hydrazinobenzyl)cephalosporins.

Some (alpha-hydrazinobenzyl)cephalosporins, I (R = Me, CH2OAc, Cl) and II (R = Me, CH2OAc), structurally related (formula; see text) to cephalexin, cephaloglycin, and cefaclor have been prepared and evaluated in vitro for their antimicrobial activity. The synthesis involves the condensation of the chloride hydrochloride III (R = H or Me) with the 7-aminocephem derivatives IV. The hydrazino compound I (R = Cl), an analogue of cefaclor, resulted in being the most active compound of the series.