Novel Design of Nonpeptide AVP V<sub>2</sub>Receptor Agonists:  Structural Requirements for an Agonist Having 1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1<i>H</i>-1-benzazepine as a Template

Kondo, Kazumi; Ogawa, Hidenori; Shinohara, Tomoichi; Kurimura, Muneaki; Tanada, Yoshihisa; Kan, Keizo; Yamashita, Hiroshi; Nakamura, Shigeki; Hirano, Takahiro; Yamamura, Yoshitaka; Mori, Toyoki; Tominaga, Michiaki; Itai, Akiko

doi:10.1021/jm000108p

Cited by 58 publications

(38 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…OPC23h, 15 WAY-VNA-932, 14 and MCF57 have a nanomolar affinity for hV 2 R and behave as full agonists for AC activation. They possess a lower affinity for hV 1a R and hOTR.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 99%

“…The Wyeth-Ayerst WAY-VNA-932 and the Otsuka OPC23h nonpeptide hV 2 R antidiuretics, 14,15 as well as a novel compound MCF57, were tested for their capacity to recruit intracellularly trapped cNDI-hV 2 Rs and to restore their functionality. In addition, we determined the capacity of the three ligands to act as hV 2 R biased agonists (i.e., their behavior in terms of Gs/AC agonism and arrestin antagonism).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

Jean-Alphonse¹,

Perkovska²,

Frantz

et al. 2009

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV 2 R). Most of these mutations lead to intracellular retention of the hV 2 R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV 2 Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV 2 R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV 2 R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV 2 R agonist pharmacochaperones promising therapeutic candidates for cNDI. The antidiuretic hormone arginine-vasopressin (AVP) is crucial for osmoregulation, cardiovascular control, and water homeostasis. The human AVP V 2 receptor (hV 2 R), localized in the principal cells of the kidney collecting duct, mediates AVP antidiuretic effect and therefore helps in maintaining physiologic plasma osmolality, blood volume, and arterial pressure. Binding of AVP to hV 2 R first triggers a cAMP signal through activation of the G protein ␣ s (Gs) subunit and adenylyl cyclase (AC). Then, the cAMP-activated protein kinase A phosphorylates aquaporin 2 water channels, resulting in their insertion into the luminal membrane of principal cells and finally to water reabsorption. 1 AVP binding to hV 2 R also induces arrestin recruitment, receptor internalization, 2 and mitogen-activated protein kinase (MAPK) activation. 3 Mutations in the hV 2 R gene lead to the X-linked congenital nephrogenic diabetes insipidus (cNDI), a rare disease characterized by the kidney's inability to concentrate urine despite normal or elevated plasma concentrations of AVP. 4 More than 200 different mutations have been described and are responsible for polyuria, a main consequence of the disease. Most of the mutant receptors (cNDIhV 2 Rs), trapped in the endoplasmic reticulum

show abstract

“…OPC23h, 15 WAY-VNA-932, 14 and MCF57 have a nanomolar affinity for hV 2 R and behave as full agonists for AC activation. They possess a lower affinity for hV 1a R and hOTR.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 99%

mentioning

confidence: 99%

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

Jean-Alphonse¹,

Perkovska²,

Frantz

et al. 2009

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…It almost reversed the effect of AVP on the water-loaded control. This may be due to several factors, such as species differences 16 or a higher blood level concentration of 3k, although we have no data to put forward to support this aspect. However, none of the other newly synthesized compounds completely reversed the effect of AVP on the water-loaded control (13 mL/4h).…”

mentioning

confidence: 82%

(4-Substituted-phenyl)-(5H-10,11-dihydro-pyrrolo [2,1-c][1,4] benzodiazepin-10-yl)-methanone derivatives as vasopressin receptor modulators

Venkatesan

Grosu

Failli

et al. 2005

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

“…Seven‐membered nitrogen heterocycles are important compounds in organic synthesis given their wide potential in pharmaceutical applications . Exhibiting biological activities towards several enzymes, G‐protein‐coupled receptors and anti‐HIV‐1 agents, benzazepine derivatives have attracted much attention –. Over the past decades, many efforts have been devoted to the synthesis of benzazepine derivatives .…”

Section: Methodsmentioning

confidence: 99%

Chemoselective and Enantioselective Hydrogenation of 2,4‐Diaryl‐3H‐benzo[b]azepines Catalyzed by Dendritic Phosphinooxazoline Iridium Complexes

Miao

Ding

et al. 2017

Asian J Org Chem

View full text Add to dashboard Cite

An asymmetric hydrogenation of 2,4‐diaryl‐3H‐benzo[b]azepines, catalyzed by dendritic phosphinooxazoline (PHOX) iridium complexes, has been developed. Only the imine group was reduced, while the C=C bond remained untouched, affording a range of chiral 2,3‐dihydro‐1H‐benzo[b]azepine derivatives with good to excellent enantioselectivity (up to 91 % ee). A slightly positive dendritic effect on catalytic reactivity (up to 10 000 TON) was observed.

show abstract

Novel Design of Nonpeptide AVP V₂Receptor Agonists: Structural Requirements for an Agonist Having 1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine as a Template

Cited by 58 publications

References 32 publications

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

(4-Substituted-phenyl)-(5H-10,11-dihydro-pyrrolo [2,1-c][1,4] benzodiazepin-10-yl)-methanone derivatives as vasopressin receptor modulators

Chemoselective and Enantioselective Hydrogenation of 2,4‐Diaryl‐3H‐benzo[b]azepines Catalyzed by Dendritic Phosphinooxazoline Iridium Complexes

Contact Info

Product

Resources

About

Novel Design of Nonpeptide AVP V2Receptor Agonists: Structural Requirements for an Agonist Having 1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine as a Template

Cited by 58 publications

References 32 publications

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

(4-Substituted-phenyl)-(5H-10,11-dihydro-pyrrolo [2,1-c][1,4] benzodiazepin-10-yl)-methanone derivatives as vasopressin receptor modulators

Chemoselective and Enantioselective Hydrogenation of 2,4‐Diaryl‐3H‐benzo[b]azepines Catalyzed by Dendritic Phosphinooxazoline Iridium Complexes

Contact Info

Product

Resources

About

Novel Design of Nonpeptide AVP V₂Receptor Agonists: Structural Requirements for an Agonist Having 1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine as a Template