ABSTRACT
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. Moreover, we have also synthesized cyclohexylpiperidines (CHPEs, 3a-d), which all showed higher binding affinities for the D(4) DAR than their aromatic counterparts. These results indicate that a pi-pi type interaction of the phenyl ring of PPEs with the D(4) DAR might not be essential, whereas a simple hydrophobic attraction between the cyclohexyl substituent of CHPEs and a hypothesized lipophilic pocket of the receptor might be crucial. Furthermore, functional assays indicate that 3d, as well as 1, are partial agonist at the D(4) DAR and therefore might represent new pharmacological tools to investigate the role of D(4) DAR activation in the control of cognitive functions and emotional states in health and disease.
Subject(s)
Dopamine Agonists/chemical synthesis , Piperidines/chemical synthesis , Receptors, Dopamine D2/drug effects , Animals , Binding, Competitive , Corpus Striatum/metabolism , Crystallography, X-Ray , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacology , Guanine Nucleotides/pharmacology , Guinea Pigs , In Vitro Techniques , Male , Melatonin/biosynthesis , Piperidines/chemistry , Piperidines/pharmacology , Purine Nucleosides , Pyrimidinones/chemistry , Pyrroles/chemistry , Radioligand Assay , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D4 , Retina/metabolism , Structure-Activity RelationshipABSTRACT
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. This fact may be seen from a comparison of the MIC values with those of the minimum fungicidal concentration (MFC) values for most of the type 7 compounds assayed that have shown differences between the MIC and the MFC, which are lower than three double diluitions. A simple molecular modeling of the P450 14-alpha-sterol demethylase from C. albicans (Candida P450DM) was built in order to understand how the structural differences between type 7 compounds and oxiconazole 6 can induce different antifungal profiles. The results of this work seem to confirm that it is possible to reverse the atomic sequence of the methyleneaminoxy group, C=N-O, of 6, obtaining new imidazoles possessing good antifungal properties.
Subject(s)
Antifungal Agents/chemical synthesis , Ethers/chemical synthesis , Imidazoles/chemical synthesis , Oximes/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Aspergillus fumigatus/drug effects , Candida/drug effects , Candida/enzymology , Cryptococcus neoformans/drug effects , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/genetics , Ethers/chemistry , Ethers/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Oxidoreductases/chemistry , Oxidoreductases/genetics , Oximes/chemistry , Oximes/pharmacology , Recombinant Fusion Proteins/chemistry , Sterol 14-Demethylase , Structure-Activity Relationship , Trichophyton/drug effectsABSTRACT
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. The compound with the highest in vitro activity towards COX-2 (9) was also assayed in vivo for its antiinflammatory activity by means of the carrageenan-induced paw edema test in rats. Some of the new compounds showed an appreciable in vitro COX-2 inhibitory activity, with IC(50) values in the microM (6,7,9,10,11) range. Compound 9 also exhibited an appreciable in vivo activity (29% inhibition at a dose of 30 mg kg(-1)) when administered intraperitoneally. The structural parameters of 9 were determined by X-ray crystallographic analysis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclooxygenase Inhibitors/chemical synthesis , Cyclopentanes/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Isoenzymes/antagonists & inhibitors , Sulfhydryl Compounds/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Carrageenan , Cell Line , Crystallography, X-Ray , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Cyclooxygenase Inhibitors/therapeutic use , Cyclopentanes/pharmacology , Edema/chemically induced , Edema/drug therapy , Heterocyclic Compounds, 2-Ring/pharmacology , Heterocyclic Compounds, 2-Ring/therapeutic use , Macrophages/drug effects , Macrophages/metabolism , Membrane Proteins , Models, Molecular , Prostaglandin-Endoperoxide Synthases , Rats , Sulfhydryl Compounds/pharmacologyABSTRACT
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). Comparison of the affinity and activity data of novel derivatives with those of reference compounds 2, 3 and 4 shows a general low ability of DDSNPs 5 and 6 to interact with both alpha and beta- adrenoceptors.
