2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity.
A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.
Yardley
J P
JP
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Husbands
G E
GE
Stack
G
G
Butch
J
J
Bicksler
J
J
Moyer
J A
JA
Muth
E A
EA
Andree
T
T
Fletcher
H
H
James
M N
MN
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001667:Binding, Competitive; D001681:Biological Assay; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003461:Crystallography; D007035:Hypothermia / Q000139:chemically induced; D007099:Imipramine / Q000378:metabolism; D066298:In Vitro Techniques; D008958:Models, Molecular; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012110:Reserpine / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000928:Antidepressive Agents; D018377:Neurotransmitter Agents; D010627:Phenethylamines; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D012701:Serotonin; D012110:Reserpine; D000324:Adrenocorticotropic Hormone; D007099:Imipramine; D009638:Norepinephrine