Synthesis of Chiral 1-[ω-(4-Chlorophenoxy)alkyl]-4-methylpiperidines and Their Biological Evaluation at σ 1 , σ 2 , and Sterol Δ 8 −Δ 7 Isomerase Sites
2003; American Chemical Society; Volume: 46; Issue: 11 Linguagem: Inglês
10.1021/jm021014d
ISSN1520-4804
AutoresFrancesco Berardi, Fulvio Loiodice, Giuseppe Fracchiolla, Nicola Antonio Colabufo, Roberto Perrone, Vincenzo Tortorella,
Tópico(s)Phenothiazines and Benzothiazines Synthesis and Activities
ResumoSumitomo's patented σ 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 σ1, σ2, and sterol Δ8−Δ7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective σ1 binding relative to other σ family sites. Generally high σ1-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 σ1 selectivity. However, the (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine ((−)-(S)-17) reached the highest σ1 affinity (Ki = 0.34 nM) and the best selectivity relative to the σ2 site (547-fold). Compound (−)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.
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