Synthesis of chiral 1-[omega-(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at sigma1, sigma2, and sterol delta8-delta7 isomerase sites.
Sumitomo's patented sigma ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at sigma1, sigma2, and sterol Delta8-Delta7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective sigma(1) binding relative to other sigma family sites. Generally high sigma1-site affinities were found, so that the chirality introduced by a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain was beneficial to increase sigma1 selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine ((-)-(S)-17) reached the highest sigma1 affinity (K(i) = 0.34 nM) and the best selectivity relative to the sigma2 site (547-fold). Compound (-)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.
Berardi
Francesco
F
Dipartimento Farmaco-Chimico, Università di Bari, via Orabona 4, I-70126 Bari, Italy. berardi@farmchim.uniba.it
Loiodice
Fulvio
F
Fracchiolla
Giuseppe
G
Colabufo
Nicola Antonio
NA
Perrone
Roberto
R
Tortorella
Vincenzo
V
D000818:Animals; D001665:Binding Sites; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D013251:Steroid Isomerases / Q000378:metabolism*; D013329:Structure-Activity Relationship
C474821:4-methyl-1-(2-(4-chlorophenoxy)-1-methylethyl)piperidine; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase