Characterization of orally active nonpeptide vasopressin V(2) receptor agonist. Synthesis and biological evaluation of both the (5R)- and (5S)-enantioisomers of 2-[1-(2-Chloro-4-pyrrolidin-1-yl-benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin- 5-yl]-N-isopropylacetamide.
The synthesis and evaluation of both the (R)- and (S)-enantioisomers about the 5-position on a tetrahydro-1H-1-benzazepine derivative were described. The absolute configuration of the (R,R)-isomer (10) was determined by X-ray crystallographic analysis. After evaluation of both enantiomers (compounds R-2, S-2) for binding affinity, cAMP accumulation, and an in vivo study using Brattleboro rats, R-2 showed more potent activity as a V(2) receptor agonist than S-2.
Kondo
Kazumi
K
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Company, 463-10 Kagasuno Kawauchi-cho, Tokushima 771-0192, Japan. k_kondo@research.otsuka.co.jp
Kan
Keizo
K
Tanada
Yoshihisa
Y
Bando
Masahiko
M
Shinohara
Tomoichi
T
Kurimura
Muneaki
M
Ogawa
Hidenori
H
Nakamura
Shigeki
S
Hirano
Takahiro
T
Yamamura
Yoshitaka
Y
Kido
Masaru
M
Mori
Toyoki
T
Tominaga
Michiaki
M
D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D011869:Radioligand Assay; D051381:Rats; D011910:Rats, Brattleboro; D017483:Receptors, Vasopressin / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D017483:Receptors, Vasopressin; D000242:Cyclic AMP