Methoxy- and fluorine-substituted analogs of O-1302: synthesis and in vitro binding affinity for the CB1 cannabinoid receptor.
Methoxy and fluorine analogs substituted on the terminal carbon of the pentyl chain of N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-pentylphenyl)-1H-pyrazole-3-carboxamide (O-1302) were synthesized in a multi-step process from 5-phenyl-1-pentanol, which was based on the 1,5-diarylpyrazole core template of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) through condensation of the respective amine with pyrazole carboxylic acid, in order to develop tracers for medical imaging. Their potency for inhibiting the binding of the CB1 antagonist [(3)H]SR141716 was evaluated with the aim of developing positron emission tomography (PET) ligands for the cerebral cannabinoid CB1 receptor. These analogs bearing a piperidinyl carboxamide at the C(3) of the pyrazole ring exhibited affinities comparable to those of the CB1 reference antagonist SR141716, which warrants further investigation using the radiolabeled form for biological imaging studies. A morpholine ring substituted at the C(3) of the pyrazole ring resulted in a reduction of the CB1 affinity.
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Shintaro
S
Tobiishi
Toru
T
Sasada
Yumiko
Y
Nojiri
Fumihiko
F
Yamamoto
Takahiro
T
Mukai
Kiichi
K
Ishiwata
Minoru
M
Maeda
D000818:Animals; D001812:Blood-Brain Barrier; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry; D005462:Fluorine Radioisotopes; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008566:Membranes / Q000378:metabolism; D008745:Methylation; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism*; D000077285:Rimonabant
D005462:Fluorine Radioisotopes; C522675:N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-pentylphenyl)-1H-pyrazole-3-carboxamide; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D005461:Fluorine; D000077285:Rimonabant