6 research outputs found
Convergent cross-species pro-cognitive effects of RGH-235, a new potent and selective histamine H3 receptor antagonist/inverse agonist
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
Convergent cross-species pro-cognitive effects of RGH-235, a new potent and selective histamine H3 receptor antagonist/inverse agonist
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 disorder (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 beneficial cognitive effects can be linked to antagonism/inverse agonism of H3 receptors
The influence of 5-HT2A activity on a 5-HT2C specific in vivo assay used for early identification of multiple acting SERT and 5-HT2C receptor ligands
As a result of our exploratory programme aimed at elaborating
dually acting compounds towards the serotonin (5-HT) transporter
(SERT) and the 5-HT2C receptor a novel series of 3-amino-1-
phenylpropoxy substituted diphenylureas was identified. From
that collection two promising compounds (2 and 3) exhibiting
highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C
receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced
hypomotility in mice. In further pursuance of that objective (2-
aminoethyl)(benzyl)sulfamoyl diphenylureas and
diphenylpiperazines have also been elaborated. Herein we report
the synthesis of potent multiple-acting compounds from this new
class. However, when two optimized representatives (6 and 14)
possessing the desired in vitro profile were tested neither
reduced the motor activity of mCPP treated animals. Comparative
albeit limited in vitro structure-activity relationship (SAR)
analysis and detailed in vivo studies are discussed and
explanation for their intricate behaviour is proposed