2 research outputs found
CB2-Selective Cannabinoid Receptor Ligands: Synthesis, Pharmacological Evaluation, and Molecular Modeling Investigation of 1,8-Naphthyridin-2(1<i>H</i>)‑one-3-carboxamides
We
have recently identified 1,8-naphthyridin-2Â(1<i>H</i>)-one-3-carboxamide
as a new scaffold very suitable for the development
of new CB2 receptor potent and selective ligands. In this paper we
describe a number of additional derivatives in which the same central
scaffold has been variously functionalized in position 1 or 6. All
new compounds showed high selectivity and affinity in the nanomolar
range for the CB2 receptor. Furthermore, we found that their functional
activity is controlled by the presence of the substituents at position
C-6 of the naphthyridine scaffold. In fact, the introduction of substituents
in this position determined a functionality switch from agonist to
antagonists/inverse agonists. Finally, docking studies showed that
the difference between the pharmacology of these ligands may be in
the ability/inability to block the Toggle Switch W6.48(258) (χ1 <i>g+</i> → <i>trans</i>) transition
Identification of the GPR55 Antagonist Binding Site Using a Novel Set of High-Potency GPR55 Selective Ligands
GPR55 is a class A G protein-coupled
receptor (GPCR) that has been
implicated in inflammatory pain, neuropathic pain, metabolic disorder,
bone development, and cancer. Initially deorphanized as a cannabinoid
receptor, GPR55 has been shown to be activated by non-cannabinoid
ligands such as l-α-lysophosphatidylinositol (LPI).
While there is a growing body of evidence of physiological and pathophysiological
roles for GPR55, the paucity of specific antagonists has limited its
study. In collaboration with the Molecular Libraries Probe Production
Centers Network initiative, we identified a series of GPR55 antagonists
using a β-arrestin, high-throughput, high-content screen of
∼300000 compounds. This screen yielded novel, GPR55 antagonist
chemotypes with IC<sub>50</sub> values in the range of 0.16–2.72
μM [Heynen-Genel, S., et al. (2010) Screening for Selective
Ligands for GPR55: Antagonists (ML191, ML192, ML193) (Bookshelf ID
NBK66153; PMID entry 22091481)]. Importantly, many of the GPR55 antagonists
were completely selective, with no agonism or antagonism against GPR35,
CB1, or CB2 up to 20 μM. Using a model of the GPR55 inactive
state, we studied the binding of an antagonist series that emerged
from this screen. These studies suggest that GPR55 antagonists possess
a head region that occupies a horizontal binding pocket extending
into the extracellular loop region, a central ligand portion that
fits vertically in the receptor binding pocket and terminates with
a pendant aromatic or heterocyclic ring that juts out. Both the region
that extends extracellularly and the pendant ring are features associated
with antagonism. Taken together, our results provide a set of design
rules for the development of second-generation GPR55 selective antagonists