Antidepressant-like activity of corticotropin-releasing factor type-1 receptor antagonists in mice.
The development of selective corticotropin-releasing factor type-1 (CRF1) receptor antagonists represents a potential novel treatment for depression. These studies evaluated CRF1 receptor antagonists for antidepressant-like activity in mice. Subchronic dosing of both R 121919 (3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine) and DMP 696 (4-(1,3-dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine) significantly decreased immobility time in the tail suspension test (at 30 and at 3 and 10 mg/kg, i.p., respectively). These antidepressant-like effects were observed at doses that did not impair general locomotor activity. Neither antalarmin (N-butyl-N-ethyl-[2,5,6-trimethyl-7-(2,4,6)trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine) nor DMP 904 (4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine) had an effect indicative of antidepressant-like activity. These results suggest that the tail suspension assay may have utility to identify CRF1 receptor antagonists with antidepressant-like activity. Moreover, the results lend support to the theory that some nonpeptidic CRF1 receptor antagonists may possess antidepressant-like activity and therefore represent a promising novel pharmacotherapeutic strategy in the treatment of depression.
Nielsen
Darci M
DM
Pfizer, Kalamazoo, MI 49007, USA.
Carey
Galen J
GJ
Gold
Lisa H
LH
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003010:Clorgyline / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D017374:Paroxetine / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D000077593:Reboxetine; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology; D013550:Swimming; D014191:Tranylcypromine / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology*
C417190:4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)pyrazolo(1,5-a)pyrimidine; D000928:Antidepressive Agents; C404928:DMP 696; D009025:Morpholines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; C103016:antalarmin; D005473:Fluoxetine; D012642:Selegiline; D014191:Tranylcypromine; D017374:Paroxetine; D000077593:Reboxetine; D003010:Clorgyline; D003891:Desipramine