Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Eur J Med Chem ; 46(4): 1207-21, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21330016

ABSTRACT

Bivalent ligands constituted by two identical pharmacophores structurally related to the Nociceptin Opioid Receptor (NOPr) antagonist JTC-801 were synthesized and their binding affinities for NOPr were evaluated. The novel ligands are formed by two modified JTC-801 units linked by di-iminic and di-aminic spacers with length ranging from three to ten methylene units. Moreover, the synthesis and the pharmacological characterization were extended to the corresponding univalent ligands. The latter compounds consisted in a single modified JTC-801 unit and an alkyl or alkylamino or alkylimino tail. The purpose of this study is to feature the location and surroundings of the allosteric binding site(s) of pharmacophores containing the 4-aminoquinoline structure. Most important, the bivalent ligands were exploited to reveal the eventual occurrence of a supramolecular receptorial architecture of the NOPr. All the bivalent derivatives 4 and 5 proved to be active in the nanomolar range with no outstanding dependence on the chain length. They showed potencies from three to ten times higher than the corresponding monomers. Consequently, results clearly indicated a positive role of the second pharmacophore in the ligand-protein interaction. The pharmacological profile of the monomers 7 and 8 clarified the contribution of the linker chain to NOP receptor affinity and suggested the presence of a lipophilic acidic site neighbouring the binding site of the JTC-like ligands. Selectivity of saturated compounds 5, 7, and 8 was tested by binding experiments on δ, κ and µ opioid receptors. Results indicated a general loss of selectivity as compared to JTC-801. In the [(35)S]GTPγS binding assay, all the compounds revealed antagonistic properties at the NOP Receptor. In conclusion the present study set the basis for a systematic investigation on the structural modifications that can be introduced into novel ligands for NOPr and helped to feature the surrounds of the allosteric site of NOPr.


Subject(s)
Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Narcotic Antagonists , Narcotic Antagonists/chemistry , Narcotic Antagonists/pharmacology , Aminoquinolines/chemical synthesis , Benzamides/chemical synthesis , Humans , Inhibitory Concentration 50 , Narcotic Antagonists/chemical synthesis , Receptors, Opioid , Nociceptin Receptor
2.
Bioorg Chem ; 39(1): 59-66, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21211814

ABSTRACT

The interaction of new bivalent NOP receptor antagonists with dodecyl phosphatidylcholine micelles and DMPC/cholesterol liposomes was investigated in solution by high resolution NMR. The ligands are structurally related to the NOP antagonist JTC-801 plus a propanediamine or heptanediamine spacer between the pharmacophoric units. Ligand internuclear distances were derived from 2D NOESY data and applied to molecular modelling calculations as conformational restraints. NMR experiments on micelles evidenced that the ligands closely approached the micelles but gave no hints on the preferential conformations of the interacting ligands. Results from NMR experiments in the presence of liposomes clearly indicated that both ligands strongly interacted with the bilayer assuming a preferential folded conformation with the quinoline arms superimposing on each other. The finding suggested that these strongly lipophilic pharmacophores could localize in the native receptorial membrane in the form of a depot, gaining access to the recognition site via the lipid bilayer.


Subject(s)
Lipid Bilayers/chemistry , Narcotic Antagonists/chemistry , Narcotic Antagonists/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Cholesterol/chemistry , Dimyristoylphosphatidylcholine/chemistry , Humans , Ligands , Liposomes/chemistry , Micelles , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Phosphatidylcholines/chemistry , Receptors, Opioid/metabolism , Nociceptin Receptor
3.
J Med Chem ; 51(4): 1058-62, 2008 Feb 28.
Article in English | MEDLINE | ID: mdl-18232652

ABSTRACT

Some synthesized 1,2-dihydrospiro[isoquinoline-4(3 H),4'-piperidin]-3-ones were evaluated as ligands for nociceptin receptor (NOP receptor). Their affinity was established by binding studies, and efficacy was investigated by GTP binding experiments. Selectivity toward DOP, KOP, and MOP receptors was assessed, and structural requirements affecting affinity and selectivity were remarked. Most notably, compound 6d displayed nanomolar NOP receptor affinity and showed more than 800-fold selectivity. The new structures exerted full or partial agonistic activity.


Subject(s)
Cyclohexanes/chemical synthesis , Isoquinolines/chemical synthesis , Piperidines/chemical synthesis , Receptors, Opioid/agonists , Spiro Compounds/chemical synthesis , Cell Line , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Models, Molecular , Piperidines/chemistry , Piperidines/pharmacology , Radioligand Assay , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Nociceptin Receptor
4.
Anal Biochem ; 367(1): 111-21, 2007 Aug 01.
Article in English | MEDLINE | ID: mdl-17512489

ABSTRACT

Proton nuclear magnetic resonance (NMR) spectroscopy was used to identify and quantify the metabolites present in cultured mouse fibroblast cells 3T6 in their native state and after treatment with PD166866, an inhibitor of the fibroblast growth factor receptor. Cell extracts were prepared according to the Bligh-Dyer protocol which prevents artifacts deriving from the chemical demolition of macromolecules. Also the growth medium was subjected to the same extraction procedure. The NMR approach made possible the identification and quantification of about 40 different metabolites at nanomoles/mg of protein level: the biological relevance of the variation of some metabolite levels is discussed. Our experimental procedure offers a prospective method for the evaluation of variations of the metabolic profile deriving from different biochemical treatments of these cells.


Subject(s)
Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Amino Acids/metabolism , Animals , Cell Line , Dimethyl Sulfoxide , Enzyme Inhibitors/pharmacology , Mice , Nuclear Magnetic Resonance, Biomolecular/methods , Nucleotides/metabolism , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Urea/analogs & derivatives , Urea/pharmacology
5.
Bioorg Chem ; 35(3): 243-57, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17303215

ABSTRACT

Two acetylcholinesterase (AChE) inhibitors structurally related to Tacrine, 6-methoxytacrine (1a) and 9-heptylamino-6-methoxytacrine (1b), and their interaction with Electrophorus Electricus AChE were investigated. The complete assignment of the 1H and 13C NMR spectra of 1a and 1b was performed by mono-dimensional and homo- and hetero-correlated two-dimensional NMR experiments. This study was undertaken to elucidate the interaction modes between AChE and 1a and 1b in solution, using NMR. The interaction between the two inhibitors and AChE was studied by the analysis of the motional parameters non-selective and selective spin-lattice relaxation times, thereby allowing the motional state of 1a and 1b, both free and bound with AChE, to be defined. The relaxation data pointed out the ligands molecular moiety most involved in the binding with AChE. The relevant ligand/enzyme interaction constants were also evaluated for both compounds and resulted to be 859 and 5412M(-1) for 1a and1b, respectively.


Subject(s)
Acetylcholinesterase/chemistry , Magnetic Resonance Spectroscopy/methods , Tacrine/analogs & derivatives , Tacrine/chemistry , Acetylcholinesterase/drug effects , Enzyme Activation/drug effects , Ligands , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Protons , Reference Standards , Sensitivity and Specificity , Structure-Activity Relationship , Tacrine/pharmacology
6.
Arch Pharm (Weinheim) ; 340(1): 17-25, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17206605

ABSTRACT

Substituted 4-heteroaryl-2-phenylquinolines were synthesized and tested on NK-2 and NK-3 receptors in order to get a better insight in the structure-activity relationship. On the whole, these molecules, which can be regarded as bioisosters of the NK-3 antagonist SB 218795, displayed a lower activity than the template. Ring electronic distribution and H-bond donor and acceptor positions played some role in selectivity, 2-imidazolyl substituted 2a showing affinity mainly towards NK-3 while 3-pyrazolyl substituted 4 displayed a preferential interaction with NK-2 receptor. Structural characterization of the synthesized compounds was achieved by NMR and mass techniques. Bidimensional 1H-NOESY experiments were a helpful tool for the assignment of the isomeric structures of compounds 9 and llb-c.


Subject(s)
Quinolines/chemical synthesis , Receptors, Neurokinin-2/metabolism , Receptors, Neurokinin-3/metabolism , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Feasibility Studies , Humans , Ligands , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Quinolines/chemistry , Quinolines/metabolism , Quinolines/pharmacology , Receptors, Neurokinin-2/genetics , Receptors, Neurokinin-3/genetics , Structure-Activity Relationship , Transfection
8.
Eur J Med Chem ; 39(12): 1047-57, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15571866

ABSTRACT

A series of 4-amino-2-methylquinoline and 4-aminoquinazoline derivatives, including the reference NOP antagonist JTC-801, were synthesized by an alternative pathway and their in vitro pharmacological properties were investigated. 3-Substitution of the quinoline ring resulted very critical for affinity. So 3-methyl derivative 4j showed a similar potency compared with the reference 4h while bulky lipophilic or electron withdrawing groups in the same position strongly decreased affinity. Structural and conformational requirements for affinity were outlined by NOE NMR and computational methods and suggestions for a pharmacophore model design were provided.


Subject(s)
Aminoquinolines/chemical synthesis , Benzamides/chemical synthesis , Narcotic Antagonists , Aminoquinolines/chemistry , Aminoquinolines/metabolism , Aminoquinolines/pharmacology , Benzamides/chemistry , Benzamides/metabolism , Benzamides/pharmacology , Binding, Competitive , Calorimetry , Dose-Response Relationship, Drug , GTP-Binding Proteins/metabolism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , In Vitro Techniques , Logistic Models , Molecular Conformation , Molecular Structure , Opioid Peptides/metabolism , Protein Binding , Receptors, Opioid/metabolism , Structure-Activity Relationship , Nociceptin Receptor , Nociceptin
9.
Arch Pharm (Weinheim) ; 336(3): 143-54, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12822179

ABSTRACT

A series of 1-methyl-5-(pyrazol-3- and -5-yl- and 1, 2, 4-triazol-3- and 5-yl)-1, 2, 3, 6-tetrahydropyridine derivatives structurally related to arecoline were synthesized and evaluated on M(1), M(2), and M(3) muscarinic receptors using [(3)H] pirenzepine and [(3)H] NMS as ligands. The binding affinity depended on the position and size of the substituents. The most interesting compounds were further evaluated in functional studies on isolated organs and in vivo for cholinergic side effects. Compounds 5 l and 6 i good M(1) and M(3) antagonistic properties in vitro and were devoid of cholinergic side effects in vivo.


Subject(s)
Cholinergic Agents/chemical synthesis , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Receptors, Muscarinic/drug effects , Triazoles/chemical synthesis , Animals , Atropine/pharmacology , Binding, Competitive , Cholinergic Agents/chemistry , Cholinergic Agents/pharmacology , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Ligands , Male , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , Organ Specificity , Oxotremorine/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Rabbits , Structure-Activity Relationship , Swine , Triazoles/chemistry , Triazoles/pharmacology , Urinary Bladder/drug effects , Vas Deferens/drug effects
10.
Eur J Med Chem ; 37(2): 91-109, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11858843

ABSTRACT

In order to develop new cholinesterase agents effective against Alzheimer's disease (AD) we synthesized some phenylcarbamates structurally related to Rivastigmine and evaluated their in vitro and in vivo biological activity. Among the compounds which displayed the most significant in vitro activity, 1-[1-(3-dimethylcarbamoyloxyphenyl)ethyl]piperidine (31b), in addition to a simple and cheaper synthesis, showed lower toxicity and very similar therapeutic index in comparison with Rivastigmine.


Subject(s)
Alzheimer Disease/drug therapy , Carbamates/chemistry , Carbamates/chemical synthesis , Carbamates/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Phenylcarbamates , Acetylcholinesterase/blood , Acetylcholinesterase/metabolism , Administration, Oral , Alzheimer Disease/physiopathology , Animals , Brain/drug effects , Brain/physiology , Carbamates/therapeutic use , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/therapeutic use , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Mice , Rats , Rivastigmine , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...