Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 16(4): 1049-53, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16289815

ABSTRACT

Using positron emission tomography (PET) with a specific and selective radioligand targeting nicotinic acetylcholine receptor (nAChR) would allow us to better understand various nAChR related CNS disorders. The use of radiolabeled nAChR antagonists would provide a much safer pharmacological profile, avoiding most peripheral side effects that might be generated from radiolabeled nAChR agonists even at the tracer level; thus, PET imaging with nAChR antagonists would facilitate clinical application. A potent and selective nAChR antagonist was labeled and characterized with PET in non-human primates. Its high brain uptake, high signal-to-noise ratio, and high specific binding strongly suggest a great potential to carry out imaging studies in humans. In addition, the use of a C-11 radiotracer would allow us to perform multiple PET studies in the same individual within a short time frame. The presence of an iodine atom in the molecule also allows the possibility to label with radioiodine for SPECT studies.


Subject(s)
Brain/diagnostic imaging , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Nicotinic Antagonists/pharmacokinetics , Positron-Emission Tomography/methods , Receptors, Nicotinic/drug effects , Animals , Binding, Competitive/drug effects , Brain/drug effects , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Carbon Radioisotopes , Drug Evaluation, Preclinical , Ligands , Molecular Structure , Nicotine/pharmacokinetics , Nicotinic Antagonists/chemical synthesis , Nicotinic Antagonists/chemistry , Papio , Structure-Activity Relationship , Time Factors
2.
Eur J Pharmacol ; 501(1-3): 111-9, 2004 Oct 06.
Article in English | MEDLINE | ID: mdl-15464069

ABSTRACT

Biological studies were conducted on (3R)-7-Hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist.


Subject(s)
Narcotic Antagonists/pharmacology , Piperidines/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Tetrahydroisoquinolines/pharmacology , Animals , Humans , Male , Mice , Mice, Inbred ICR , Narcotic Antagonists/chemistry , Narcotic Antagonists/metabolism , Piperidines/chemistry , Piperidines/metabolism , Protein Binding/drug effects , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , Receptors, Opioid, kappa/metabolism , Saimiri , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/metabolism , Time
SELECTION OF CITATIONS
SEARCH DETAIL
...