2 research outputs found
Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models
A series
of novel compounds with two halogen substituents have
been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine
scaffold in the quest for drug-like 5-HT<sub>2C</sub> agonists. Compound
(+)-<b>22a</b> was identified as a potent 5-HT<sub>2C</sub> receptor
agonist, with good selectivity against the 5-HT<sub>2B</sub> and the
5-HT<sub>2A</sub> receptors. ADMET assays showed that compound (+)-<b>22a</b> possessed desirable properties in terms of its microsomal
stability, and CYP and hERG inhibition, along with an excellent brain
penetration profile. Evaluation of (+)-<b>22a</b> in animal
models of schizophrenia-related behaviors revealed that it had a desirable
activity profile, as it reduced <i>d</i>-amphetamine-stimulated
hyperlocomotion in the open field test, it restored <i>d</i>-amphetamine-disrupted prepulse inhibition, it induced cognitive
improvements in the novel object recognition memory test in NR1-KD
animals, and it produced very little catalepsy relative to haloperidol.
These data support the further development of (+)-<b>22a</b> as a drug candidate for the treatment of schizophrenia
Optimization of 2‑Phenylcyclopropylmethylamines as Selective Serotonin 2C Receptor Agonists and Their Evaluation as Potential Antipsychotic Agents
The
discovery of a new series of compounds that are potent, selective
5-HT<sub>2C</sub> receptor agonists is described herein as we continue
our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold.
Modifications focused on the alkoxyl substituent present on the aromatic
ring led to the identification of improved ligands with better potency
at the 5-HT<sub>2C</sub> receptor and excellent selectivity against
the 5-HT<sub>2A</sub> and 5-HT<sub>2B</sub> receptors. ADMET studies
coupled with a behavioral test using the amphetamine-induced hyperactivity
model identified four compounds possessing drug-like profiles and
having antipsychotic properties. Compound (+)-<b>16b</b>, which
displayed an EC<sub>50</sub> of 4.2 nM at 5-HT<sub>2C</sub>, no activity
at 5-HT<sub>2B</sub>, and an 89-fold selectivity against 5-HT<sub>2A</sub>, is one of the most potent and selective 5-HT<sub>2C</sub> agonists reported to date. The likely binding mode of this series
of compounds to the 5-HT<sub>2C</sub> receptor was also investigated
in a modeling study, using optimized models incorporating the structures
of β<sub>2</sub>-adrenergic receptor and 5-HT<sub>2B</sub> receptor