Dual NK(1) antagonists--serotonin reuptake inhibitors as potential antidepressants. Part 2: SAR and activity of benzyloxyphenethyl piperazine derivatives.
The synthesis, structure-affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK(1) antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK(1) receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants.
Ryckmans
Thomas
T
Chemical Research, R&D, UCB Pharma SA, Chemin du Foriest, B-1420, Braine-l'Alleud, Belgium. thomas_ryckmans@sandwich.pfizer.com
Berton
Olivier
O
Grimée
Renée
R
Kogej
Thierry
T
Lamberty
Yves
Y
Pasau
Patrick
P
Talaga
Patrice
P
Genicot
Christophe
C
D000438:Alcohols / Q000138:chemical synthesis / Q000494:pharmacology; D018687:Antidepressive Agents, Second-Generation / Q000138:chemical synthesis* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000438:Alcohols; D018687:Antidepressive Agents, Second-Generation; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human; C471989:benzyloxyphenethyl piperazine