Tricyclic CNS active agents by intramolecular Oxa-Pictet-Spengler reaction.
Mitsunobu inversion of the (S)-configurated lactate (S)-7, which is prepared in four steps starting from (S)-tyrosine, leads to the (R)-configurated lactate (R)-7. The key step in the transformation of the enantiomeric lactates (S)-7 and (R)-7 into the benzomorphan analogous tricycles (R,S)-16a,b, (S,R)-16a,b, (S,S)-22, and (R,R)-22 is an intramolecular Oxa-Pictet-Spengler reaction: The amides (S)-13, (R)-13, (S)-19 and (R)-19, in which the carbonyl moiety-masked as an acetal-is linked to the 2-phenylethanol moiety, are cyclized to give the tricyclic amides (R,S)-15, (S,R)-15, (S,S)-21, and (R,R)-21, respectively. In a concentration of 100 microM both enantiomers of 16a, 16b, and 22 are not able to compete with 3H-(+)-MK 801 for the phencyclidine binding sites of NMDA receptors. In vivo, only (R,S)-16b and (S,S)-22 exhibit weak sedative and analgesic activity.
Wünsch
B
B
Institut für Pharmazie und Lebensmittelchemie, Universität München, Germany.
Zott
M
M
Höfner
G
G
Bauschke
G
G
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D017478:Receptors, Phencyclidine / Q000187:drug effects / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D002491:Central Nervous System Agents; D011083:Polycyclic Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine