Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450.
1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate (R278995/CRA0450) is a newly synthesized corticotropin-releasing factor subtype 1 (CRF(1)) receptor antagonist. In the present study, in vitro and in vivo pharmacological profiles of R278995/CRA0450 were investigated. R278995/CRA0450 showed high affinity for recombinant and native CRF(1) receptors without having affinity for the CRF(2) receptor. R278995/CRA0450 attenuated CRF-induced cyclic AMP formation in AtT-20 cells and CRF-induced forepaw treading in gerbils, indicating that R278995/CRA0450 is an antagonist of the CRF(1) receptor. In addition to CRF(1) receptor antagonism, R278995/CRA0450 showed high affinity for the sigma(1) receptor, and attenuated (+)-SKF10,047-induced head-weaving behavior, suggesting sigma(1) receptor antagonism. R278995/CRA0450 showed dose-dependent in vivo occupancy when assessed by ex vivo receptor binding, indicating good brain penetration. R278995/CRA0450 did not alter spontaneous anxiety when tested in the rat elevated plus maze (up to 3 mg/kg, p.o.) or lick suppression test (up to 10 mg/kg, i.p.). However, potent anxiolytic-like properties were observed in rats subjected to swim stress prior to testing on the elevated plus-maze, indicating activity primarily in tests taxing stress-induced anxiety. R278995/CRA0450 was inactive in mouse tail suspension, rat forced swim and rat differential-reinforcement-of-low-rate 72-s (DRL72), while it showed dose-dependent antidepressant-like effects in the rat learned helplessness paradigm and the olfactory bulbectomy model, demonstrating activity in a subset of animal models of depression associated with subchronic stress exposure. No or only mild effects were seen in tests of locomotor activity, motor coordination and sedation. These results indicate that R278995/CRA0450 is an orally active CRF(1) and sigma(1) receptor antagonist with potent anxiolytic-like and antidepressant-like activities.
Chaki
Shigeyuki
S
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. s.chaki@po.rd.taisho.co.jp
Nakazato
Atsuro
A
Kennis
Ludo
L
Nakamura
Masato
M
Mackie
Claire
C
Sugiura
Masayuki
M
Vinken
Petra
P
Ashton
David
D
Langlois
Xavier
X
Steckler
Thomas
T
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000737:chemistry; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000737:chemistry; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000737:chemistry; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D006168:Guinea Pigs; D006380:Helplessness, Learned; D008252:Macaca fascicularis; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012756:Sheep; D013312:Stress, Physiological / Q000188:drug therapy / Q000378:metabolism; D000099052:CRF Receptor, Type 1
C491550:1-(8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001557:Benzenesulfonates; D011804:Quinolines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1