3 research outputs found
Identification of Novel α4β2-Nicotinic Acetylcholine Receptor (nAChR) Agonists Based on an Isoxazole Ether Scaffold that Demonstrate Antidepressant-like Activity
There is considerable evidence to support the hypothesis
that the
blockade of nAChR is responsible for the antidepressant action of
nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist,
mecamylamine, has been shown to be an effective add-on in patients
that do not respond to selective serotonin reuptake inhibitors. This
suggests that nAChR ligands may address an unmet clinical need by
providing relief from depressive symptoms in refractory patients.
In this study, a new series of nAChR ligands based on an isoxazole-ether
scaffold have been designed and synthesized for binding and functional
assays. Preliminary structure–activity relationship (SAR) efforts
identified a lead compound <b>43</b>, which possesses potent
antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical
mouse forced swim test. Early stage absorption, distribution, metabolism,
excretion, and toxicity (ADME-Tox) studies also suggested favorable
drug-like properties, and broad screening toward other common neurotransmitter
receptors indicated that compound <b>43</b> is highly selective
for nAChRs over the other 45 neurotransmitter receptors and transporters
tested
Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile
Despite their discovery in the early 20th century and
intensive study over the last 20 years, nicotinic acetylcholine receptors
(nAChRs) are still far from being well understood. Only a few chemical
entities targeting nAChRs are currently undergoing clinical trials,
and even fewer have reached the marketplace. In our efforts to discover
novel and truly selective nAChR ligands, we designed and synthesized
a series of chiral cyclopropane-containing α4β2-specific
ligands that display low nanomolar binding affinities and excellent
subtype selectivity while acting as partial agonists at α4β2–nAChRs.
Their favorable antidepressant-like properties were demonstrated in
the classical mouse forced swim test. Preliminary ADMET studies and
broad screening toward other common neurotransmitter receptors were
also carried out to further evaluate their safety profile and eliminate
their potential off-target activity. These highly potent cyclopropane
ligands possess superior subtype selectivity compared to other α4β2-nAChR
agonists reported to date, including the marketed drug varenicline,
and therefore may fully satisfy the crucial prerequisite for avoiding
adverse side effects. These novel chemical entities could potentially
be advanced to the clinic as new drug candidates for treating depression
Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile
Despite their discovery in the early 20th century and
intensive study over the last 20 years, nicotinic acetylcholine receptors
(nAChRs) are still far from being well understood. Only a few chemical
entities targeting nAChRs are currently undergoing clinical trials,
and even fewer have reached the marketplace. In our efforts to discover
novel and truly selective nAChR ligands, we designed and synthesized
a series of chiral cyclopropane-containing α4β2-specific
ligands that display low nanomolar binding affinities and excellent
subtype selectivity while acting as partial agonists at α4β2–nAChRs.
Their favorable antidepressant-like properties were demonstrated in
the classical mouse forced swim test. Preliminary ADMET studies and
broad screening toward other common neurotransmitter receptors were
also carried out to further evaluate their safety profile and eliminate
their potential off-target activity. These highly potent cyclopropane
ligands possess superior subtype selectivity compared to other α4β2-nAChR
agonists reported to date, including the marketed drug varenicline,
and therefore may fully satisfy the crucial prerequisite for avoiding
adverse side effects. These novel chemical entities could potentially
be advanced to the clinic as new drug candidates for treating depression