N-oxide analogs of WAY-100635: new high affinity 5-HT(1A) receptor antagonists.
WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-desmethyl derivative DWAY 2 are well-known high affinity 5-HT(1A) receptor antagonists, which when labeled with carbon-11 (beta+; t(1/2) = 20.4 min) in the carbonyl group are effective radioligands for imaging brain 5-HT(1A) receptors with positron emission tomography (PET). In a search for new 5-HT(1A) antagonists with different pharmacokinetic and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of 1 was oxidized to the pyridinyl N-oxide, was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine-N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4, a more lipophilic (pyridinyl-6)-chloro derivative of 3, was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2-(6-bromo)aminopyridinyl-N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5, in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2, was prepared in five steps from 2-(chloroacetylamino)pyridine. N-Oxides 3-5 were found to be high affinity antagonists at 5-HT(1A) receptors, with 3 having the highest affinity and a Ki value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (LogP = 1.87) is lower than that of 1 by 1.25 LogP units while TLC and reverse phase HPLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-11 in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-11C]3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT(1A) receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation of 3 was not apparent in vivo; in cynomolgus monkey plasma radioactive metabolites of [carbonyl-11C]3 appeared less rapidly than from the radioligands [carbonyl-11C]1 and [carbonyl-11C]2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging.
Marchais-Oberwinkler
Sandrine
S
Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, NL-9713 AV Groningen, The Netherlands. s.marchais@mx.uni-saarland.de
Nowicki
Bartek
B
Pike
Victor W
VW
Halldin
Christer
C
Sandell
Johan
J
Chou
Yuan-Hwa
YH
Gulyas
Balazs
B
Brennum
Lise T
LT
Farde
Lars
L
Wikström
Håkan V
HV
D000818:Animals; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010087:Oxides / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D010087:Oxides; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide