Synthesis of conformationally restricted analogs of baclofen, a potent GABAB receptor agonist, by the introduction of a cyclopropane ring.
Conformationally restricted analogs of baclofen (2), i.e., 5, 6, and their enantiomers ent-5, and ent-6, the conformations of which were restricted by introducing a cyclopropane ring, were designed as potential GABAB receptor ligands. Reaction of (R)-epichlorohydrin [(R)-7] and (4-chlorophenyl)acetonitrile in the presence of NaNH2 in benzene/tetrahydrofuran gave chiral cyclopropane derivatives 11 and 12, which were then converted into the target compounds 5 and 6, respectively. Their corresponding enantiomers, ent-5 and ent-6, were also synthesized starting from (S)-epichlorohydrin [(S)-7].
Shuto
S
S
Graduate School of Pharmaceutical Science, Hokkaido University, Sapporo, Japan.
Shibuya
N
N
Yamada
S
S
Ohkura
T
T
Kimura
R
R
Matsuda
A
A
D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D011487:Protein Conformation; D051381:Rats; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
D003521:Cyclopropanes; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D001418:Baclofen