12 research outputs found
Scalable, One-Pot, Microwave-Accelerated Tandem Synthesis of Unsymmetrical Urea Derivatives
We
report a facile, microwave-accelerated, one-pot tandem synthesis
of unsymmetrical ureas via a Curtius rearrangement. In this method,
one-pot microwave irradiation of commercially available (hetero)Âaromatic
acids and amines in the presence of diphenylphosphoryl azide enabled
extremely rapid (1–5 min) construction of an array of unsymmetrical
ureas in good to excellent yields. We demonstrate the utility of our
method in the efficient, gram-scale synthesis of key biologically
active compounds targeting the cannabinoid 1 and α7 nicotinic
acetylcholine receptors
Expeditious Synthesis, Enantiomeric Resolution, and Enantiomer Functional Characterization of (4-(4-Bromophenyl)-3a,4,5,9b-tetrahydro‑3<i>H</i>‑cyclopenta[<i>c</i>]quinoline-8-sulfonamide (4BP-TQS): An Allosteric Agonist-Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors
An
expeditious microwave-assisted synthesis of 4BP-TQS, its enantiomeric
separation, and their functional evaluation is reported. Electrophysiological
characterization in Xenopus oocytes
revealed that activity exclusively resided in the (+)-enantiomer <b>1b</b> (GAT107) and (−)-enantiomer <b>1a</b> did
not affect its activity when coapplied. X-ray crystallography studies
revealed the absolute stereochemistry of <b>1b</b> to be 3a<i>R</i>,4<i>S</i>,9b<i>S</i>. <b>1b</b> represents the most potent ago-PAM of α7 nAChRs available
to date and is considered for further in vivo evaluation
Protective effect of AM841 (0.1 mg/kg, i.p.) injected once daily for 3 days on TNBS-induced colitis in mice.
<p>Figure shows data for (A) macroscopic score, (B) MPO activity, (C) ulcer score and (D) body weight. $p<0.001, as compared with control animals. **p<0.01, ***p<0.001, as compared with TNBS-treated mice. Data represent means ± SEM, n = 6–8.</p
Protective effect of CB 13 after central (0.1 µg/animal, i.c.v, OD), but not peripheral (0.1 mg/kg, i.p., OD) administration for 3 days on TNBS-induced colitis in mice.
<p>Figure shows data for (A) macroscopic score, (B) MPO activity and (C) ulcer score. **p<0.01, as compared with TNBS-treated mice. Data represent means ± SEM, n = 6–8.</p
AM841 (0.1 mg/kg, i.p.) injected once daily for 7 days did not alter DSS-induced colitis in (A) CB1<sup>-/-</sup>, (B) CB2<sup>-/-</sup> (C) and CB1/CB2<sup>-/-</sup> mice.
<p>Figure shows data for macroscopic score and MPO activity. p<0.001, as compared with control animals. Data represent means ± SEM, n = 6–8.</p
Protective effect of AM841 (0.01, 0.1 and 1 mg/kg, i.p.) injected once daily for 7 days on DSS-induced colitis in mice.
<p>Figure shows data for (A) macroscopic score, (B) MPO activity, (C) body weight, (D) representative micrographs for hematoxylin and eosin staining of colon wall sections (i, control; ii, DSS; iii, DSS+AM841 0.01 mg/kg; iv, DSS+AM841 0.1 mg/kg; v, DSS+AM841 1 mg/kg; scale bar = 100 µm) and (E) microscopic score. $p<0.001, as compared with control animals. *p<0.05, ***p<0.001, as compared with DSS-treated mice. Data represent means ± SEM, n = 6–8.</p
Therapeutic effect of AM841 (0.1 mg/kg, i.p.) injected once or twice daily from day 4 on DSS-induced colitis in mice.
<p>Figure shows data for (A) macroscopic score, (B) MPO activity and (C) body weight. $p<0.001, as compared with control animals. *p<0.05, **p<0.01, as compared with DSS-treated mice. Data represent means ± SEM, n = 6–8.</p
Chemotactic assay with murine neutrophils.
<p>AM841 (0.1–100 nM) inhibited neutrophil migration to 10 nM fMLP in a concentration-dependent manner. p<0.001, as compared with vehicle-treated controls. Data represent means ± SEM of 4 independent experiments performed in duplicate.</p
New Alpha9 nAChR Ligands Based on a 5‑(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold
Several lines of evidence have indicated
that nicotinic
acetylcholine
receptors (nAChR) that contain α9 subunits, probably in combination
with α10 subunits, may be valuable targets for the management
of
pain associated with inflammatory diseases through a cholinergic anti-inflammatory
system (CAS), which has also been associated with α7 nAChR.
Both α7- and α9-containing neuronal nAChR can be pharmacologically
distinguished from the high-affinity nicotinic receptors of the brain
by their sensitivity to α-bungarotoxin, but in other ways, they
have quite distinct pharmacological profiles. The early association
of α7 with CAS led to the development of numerous new ligands,
variously characterized as α7 agonists, partial agonists, or
silent agonists that desensitized α7 receptors without activation.
Subsequent reinvestigation of one such family of α7 ligands
based on an N,N-diethyl-N′-phenylpiperazine scaffold led to the identification
of potent agonists and antagonists for α9. In this paper, we
characterize the α9/α10 activity of a series of compounds
based on a 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole (QMO) scaffold
and identify two new potent ligands of α9, QMO-28, an agonist,
and QMO-17, an antagonist. We separated the stereoisomers of these
compounds to identify the most potent agonist and discovered that
only the 3R isomer of QMO-17 was an α9 antagonist,
permitting an in silico model of α9 antagonism
to be developed. The α9 activity of these compounds was confirmed
to be potentially useful for CAS management of inflammatory pain in
cell-based assays of cytokine release
Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor
The
cannabinoid 1 receptor (CB1R) is one of the most widely expressed
metabotropic G protein-coupled receptors in brain, and its participation
in various (patho)Âphysiological processes has made CB1R activation
a viable therapeutic modality. Adverse psychotropic effects limit
the clinical utility of CB1R orthosteric agonists and have promoted
the search for CB1R positive allosteric modulators (PAMs) with the
promise of improved drug-like pharmacology and enhanced safety over
typical CB1R agonists. In this study, we describe the synthesis and <i>in vitro</i> and <i>ex vivo</i> pharmacology of the
novel allosteric CB1R modulator GAT211 (racemic) and its resolved
enantiomers, GAT228 (<i>R</i>) and GAT229 (<i>S</i>). GAT211 engages CB1R allosteric site(s), enhances the binding of
the orthosteric full agonist [<sup>3</sup>H]ÂCP55,490, and reduces
the binding of the orthosteric antagonist/inverse agonist [<sup>3</sup>H]ÂSR141716A. GAT211 displayed both PAM and agonist activity in HEK293A
and Neuro2a cells expressing human recombinant CB1R (hCB1R) and in
mouse-brain membranes rich in native CB1R. GAT211 also exhibited a
strong PAM effect in isolated vas deferens endogenously expressing
CB1R. Each resolved and crystallized GAT211 enantiomer showed a markedly
distinctive pharmacology as a CB1R allosteric modulator. In all biological
systems examined, GAT211’s allosteric agonist activity resided
with the <i>R-</i>(+)-enantiomer (GAT228), whereas its PAM
activity resided with the <i>S</i>-(−)-enantiomer
(GAT229), which lacked intrinsic activity. These results constitute
the first demonstration of enantiomer-selective CB1R positive allosteric
modulation and set a precedent whereby enantiomeric resolution can
decisively define the molecular pharmacology of a CB1R allosteric
ligand