RXFP1 Agonist

A cell-permeable 2-acetamido-N-phenylbenzamide that selectively activates human, but not mouse, LGR7/RXFP1 (EC₅₀ = 94 and 200 nM, respectively, in cAMP induction using HEK293-hRXFP1 transfectant and THP1) via allosteric interaction with the ECL3 (TM helix 5 to EC loop3; V646 to T660) region without competing against ECL2-mediated relaxin binding, while exhibiting cytotoxicity only at much higher concentrations (IC₅₀ in 72 h = 9.4 µM in HEK293-RXFP1 cultures) and displaying no activity toward AVPR1B- (Arginine vasopressin receptor 1B) or LGR8/RXFP2-mediated cAMP induction. Although shown to be ~150-fold and 500-fold less potent than relaxin (RLX), respectively, in VEGF mRNA induction (275% of basal level in THP1 cells; 250 nM) and cellular impedance assays (in HEK293-RXFP1 cultures), pharmacokinetic studies reveal superior in vivo stability (T_1/2 = 8.56 and 7.48 h in plasma and heart post single 30 mg/kg i.p. dosage in mice) to RLX (initial T_1/2<10 min in human; i.v.) and, while RLX is not orally active, this chemical agonist is demonstrated to be bioavailable in mice via oral (C_max/T_max = 604 nM/1 h and 1026 ng/g/1.5 h in plasma and heart, respectively; 30 mg/kg) or intraperitoneal (C_max/T_max = 9.29 µM/1 h and 28.6 µmol/kg/1 h in plasma and heart, respectively; 30 mg/kg) administration in vivo with good aqueous solubility (7 µM in PBS).

A cell-permeable 2-acetamido-N-phenylbenzamide that selectively activates human, but not mouse, LGR7/RXFP1-mediated cAMP induction (EC₅₀ = 200 nM in THP1) via allosteric interaction with the ECL3 region without competing against ECL2-mediated relaxin binding or affecting AVPR1B- or LGR8/RXFP2-mediated cAMP induction. Although shown to be ~150-fold and 500-fold less potent than relaxin (RLX), respectively, in VEGF mRNA induction and cellular impedance assays, pharmacokinetic studies reveal superior in vivo stability to RLX and in vivo bioavailability in mice via oral (C_max/T_max = 604 nM/plasma/1 h and 1026 ng/g heart/1.5 h; 30 mg/kg) or intraperitoneal (C_max/T_max = 9.29 µM/plasma/1 h and 28.6 µmol/kg heart/1 h; 30 mg/kg) administration with good aqueous solubility (7 µM in PBS).

Cell permeable: yes

Primary Target
hRXFP1

Reversible: yes

Packaged under inert gas

Toxicity: Standard Handling (A)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Xiao, J., et al. 2013. Nat. Commun.4, 1953.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany