32 research outputs found
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
Test ages for behavioral work, broken down by test cohort.
<p>Test ages for behavioral work, broken down by test cohort.</p
Proportion of mice climbing in the rearing climbing assay in the wild type, heterozygous and homozygous group during the dark phase of the diurnal cycle.
<p>Proportion of mice climbing in the rearing climbing assay in the wild type, heterozygous and homozygous group during the dark phase of the diurnal cycle.</p
Qualitative Polymerase Chain Reaction (qPCR) information.
<p>Qualitative Polymerase Chain Reaction (qPCR) information.</p
Rearing frequency in the Open Field (mean ± SEM) of wild type, heterozygous and homozygous mice as a function of age during the dark phase of the diurnal cycle.
<p>Rearing frequency in the Open Field (mean ± SEM) of wild type, heterozygous and homozygous mice as a function of age during the dark phase of the diurnal cycle.</p
Kaplan-Meier survival curve in WT vs. homozygous mice as a function of genotype and age.
<p>Kaplan-Meier survival curve in WT vs. homozygous mice as a function of genotype and age.</p
Latency to fall from the rotarod (mean ± SEM) of wild type, heterozygous and homozygous mice as a function of age during the dark phase of the diurnal cycle.
<p>Latency to fall from the rotarod (mean ± SEM) of wild type, heterozygous and homozygous mice as a function of age during the dark phase of the diurnal cycle.</p
Overall visit frequency during PhenoCube testing at 37 weeks, broken down into 1 hour bins (A) and summarized across the two complete light/dark periods from lights-on on day 2 (B).
<p>Overall visit frequency during PhenoCube testing at 37 weeks, broken down into 1 hour bins (A) and summarized across the two complete light/dark periods from lights-on on day 2 (B).</p
Total distance covered in the Open Field per 5 minute bin (mean ± SEM) of wild type, heterozygous and homozygous mice as a function of age and test time during the dark phase of the diurnal cycle.
<p>Total distance covered in the Open Field per 5 minute bin (mean ± SEM) of wild type, heterozygous and homozygous mice as a function of age and test time during the dark phase of the diurnal cycle.</p