Novel specific inverse agonist of GHSR1a receptor

MARTINEZ DAMONTE V, LOPEZ SOTO J, CORNEJO P, FERNÁNDEZ J, GARCIA ROMERO G, REYNALDO M, RODRIGUEZ S, PERELLÓ M, MARIE J, RAINGO J

Mar del Plata

Congreso; XXX Congreso de la Sociedad Argentina de Investigación en Neurociencias; 2015

GHSR1a is a G protein coupled receptor with constitutive activity (CA) that modulates neuronal circuits that control appetite. Thus, its inverse agonists are potential therapeutic agents that could lower the set point for hunger. Substance P analog (SP) has been extensively used in research to reduce GHSR1a CA but this peptide is highly unspecific.Therefore, there is a great interest in developing specific GHSR1a inverse agonists. Here wepresent a compelling study of JMV4957, a new compound recently synthetized withpotential GHSR1a inverse agonist properties.We first tested if JMV4957 is capable of binding GHSR1a in HEK293t transfected cells, and found that it has a high binding affinity (Ka=28 nM). Next we explored the inverse agonist effect of JMV4957 and found that this compound induced a 20% reduction of the basal inositol phosphate production with a EC50=35nM in HEK293t cells expressing GHSR1a.Moreover, we explored the effect of JMV4957 on the previously described inhibitory effect of GHSR1a CA on voltage-gated calcium channels basal currents (ICa) and surface channel expression. We found that pre-incubation with JMV4957 avoided this effect in the same manner as SP. We also performed imaging experiments and found that JMV4957 recovers channel surface density to control values in cells transfected with GHSR1a and GFP tagged channels. We are currently testing JMV4957 effect on ghrelin-induced food intake on mic