The histamine H3 receptor is a favourable target for the treatment of cognitive deficits.
Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective,
and orally active H3 receptor antagonist/inverse agonist developed by Gedeon Richter
Plc. Radioligand binding and functional assays were used for in vitro profiling. Procognitive
efficacy was investigated in rodent cognitive tests, in models of attention deficit
hyperactive dis- order (ADHD) and in cognitive tests of high translational value (rat
touch screen visual discrimination test, primate fixed-foreperiod visual reaction
time task). Results were supported by pharmacokinetic studies, neurotransmitter release,
sleep EEG and dipsogenia. RGH-235 displayed high affinity to H3 receptors (Ki = 3.0–9.2
nM, depending on species), without affinity to H1, H2 or H4 receptors and >100 other
targets. RGH-235 was an inverse agonist ([35S] GTPγS binding) and antagonist (pERK1/2
ELISA), showing favourable kinetics, inhibition of the imetit-induced dipsogenia and
moderate effects on sleep-wake EEG. RGH-235 stimulated neurotransmitter release both
in vitro and in vivo. RGH-235 was active in spontaneously hypertensive rats (SHR),
generally considered as a model of ADHD, and revealed a robust pro-cognitive profile
both in rodent and primate tests (in 0.3–1 mg/kg) and in models of high translational
value (e.g. in a rodent touch screen test and in non- human primates). The multiple
and convergent procognitive effects of RGH-235 support the view that benefi- cial
cognitive effects can be linked to antagonism/inverse agonism of H3 receptors.
