8 research outputs found
Toward the Development of Bivalent Ligand Probes of Cannabinoid CB1 and Orexin OX1 Receptor Heterodimers
Cannabinoid CB1 and orexin OX1 receptors
have been suggested to
form heterodimers and oligomers. Aimed at studying these complexes,
a series of bivalent CB1 and OX1 ligands combining SR141716 and ACT-078573
pharmacophores were designed, synthesized, and tested for activity
against CB1 and OX1 individually and in cell lines that coexpress
both receptors. Compound <b>20</b> showed a robust enhancement
in potency at both receptors when coexpressed as compared to individually
expressed, suggesting possible interaction with CB1-OX1 dimers. Bivalent
ligands targeting CB1-OX1 receptor dimers could be potentially useful
as a tool for further exploring the roles of such heterodimers in
vitro and in vivo
Truncated Orexin Peptides: Structure–Activity Relationship Studies
Orexin receptors are involved in
many processes including energy
homeostasis, wake/sleep cycle, metabolism, and reward. Development
of potent and selective ligands is an essential step for defining
the mechanism(s) underlying such critical processes. The goal of this
study was to further investigate the structure–activity relationships
of these peptides and to identify the truncated form of the orexin
peptides active at OX<sub>1</sub>. Truncation studies have led to
OXA (17–33) as the shortest active peptide known to date with
a 23-fold selectivity for OX<sub>1</sub> over OX<sub>2</sub>. Alanine, d-amino acid, and proline scans have highlighted the particular
importance of Tyr<sup>17</sup>, Leu<sup>20</sup>, Asn<sup>25</sup>, and His<sup>26</sup> for agonist properties of OXA(17–33).
The conformation of the C-terminus might also be a defining factor
in agonist activity and selectivity of the orexin peptides for the
OX<sub>1</sub> receptor
Diarylureas as Allosteric Modulators of the Cannabinoid CB1 Receptor: Structure–Activity Relationship Studies on 1‑(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1)
The recent discovery of allosteric
modulators of the CB1 receptor
including PSNCBAM-1 (<b>4</b>) has generated significant interest
in CB1 receptor allosteric modulation. Here in the first SAR study
on <b>4</b>, we have designed and synthesized a series of analogs
focusing on modifications at two positions. Pharmacological evaluation
in calcium mobilization and binding assays revealed the importance
of alkyl substitution at the 2-aminopyridine moiety and electron deficient
aromatic groups at the 4-chlorophenyl position for activity at the
CB1 receptor, resulting in several analogs with comparable potency
to <b>4</b>. These compounds increased the specific binding
of [<sup>3</sup>H]CP55,940, in agreement with previous reports. Importantly, <b>4</b> and two analogs dose-dependently reduced the <i>E</i><sub>max</sub> of the agonist curve in the CB1 calcium mobilization
assays, confirming their negative allosteric modulator characteristics.
Given the side effects associated with CB1 receptor orthosteric antagonists,
negative allosteric modulators provide an alternative approach to
modulate the pharmacologically important CB1 receptor
Synthesis and Evaluation of Metabotropic Glutamate Receptor Subtype 5 Antagonists Based on Fenobam
In an effort to discover potent and selective metabotropic
glutamate
receptor subtype 5 (mGluR5) antagonists, 15 tetrahydropyrimidinone
analogues of 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-4,5-dihydro-1<i>H</i>-imidazol-2-yl)-urea (fenobam) were synthesized. These
compounds were evaluated for antagonism of glutamate-mediated mobilization
of internal calcium in an mGluR5 in vitro efficacy assay. The IC<sub>50</sub> value for 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-1,4,5,6-tetrahydropyridine)urea
(<b>4g</b>) was essentially identical to that of fenobam
Effect of 1‑Substitution on Tetrahydroisoquinolines as Selective Antagonists for the Orexin‑1 Receptor
Selective
blockade of the orexin-1 receptor (OX<sub>1</sub>) has
been suggested as a potential approach to drug addiction therapy because
of its role in modulating the brain’s reward system. We have
recently reported a series of tetrahydroisoquinoline-based OX<sub>1</sub> selective antagonists. Aimed at elucidating structure–activity
relationship requirements in other regions of the molecule and further
enhancing OX<sub>1</sub> potency and selectivity, we have designed
and synthesized a series of analogues bearing a variety of substituents
at the 1-position of the tetrahydroisoquinoline. The results show
that an optimally substituted benzyl group is required for activity
at the OX<sub>1</sub> receptor. Several compounds with improved potency
and/or selectivity have been identified. When combined with structural
modifications that were previously found to improve selectivity, we
have identified compound <b>73</b> (RTIOX-251) with an apparent
dissociation constant (<i>K</i><sub>e</sub>) of 16.1 nM
at the OX<sub>1</sub> receptor and >620-fold selectivity over the
OX<sub>2</sub> receptor. In vivo, compound <b>73</b> was shown
to block the development of locomotor sensitization to cocaine in
rats
Identification of 1‑({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)‑1<i>H</i>‑pyrazol-3-yl]carbonyl}amino)cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound
Compounds
active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects
on different types of nociceptive modalities, including thermal, mechanical,
and chemical stimuli. The NTS2 preferring peptide JMV-431 (<b>2</b>) and the NTS2 selective nonpeptide compound levocabastine (<b>6</b>) have been shown to be effective in relieving the pain associated
with peripheral neuropathies. With the aim of identifying novel nonpeptide
compounds selective for NTS2, we examined analogues of SR48692 (<b>5a</b>) using a FLIPR calcium assay in CHO cells stably expressing
rat NTS2. This led to the discovery of the NTS2 selective nonpeptide
compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1<i>H</i>-pyrazol-3-yl]carbonyl}amino)cyclohexane carboxylic acid (NTRC-739, <b>7b</b>) starting from the nonselective compound <b>5a</b>
Discovery of <i>N</i>‑{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists
There is continuing interest in the
discovery and development of
new κ opioid receptor antagonists. We recently reported that
N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class
of opioid receptor antagonists. In this study, we report the syntheses
of two piperazine JDTic-like analogues. Evaluation of the two compounds
in an in vitro [<sup>35</sup>S]GTPγS binding assay showed that
neither compound showed the high potency and κ opioid receptor
selectivity of JDTic. A library of compounds using the core scaffold <b>21</b> was synthesized and tested for their ability to inhibit
[<sup>35</sup>S]GTPγS binding stimulated by the selective κ
opioid agonist U69,593. These studies led to <i>N</i>-[(1<i>S</i>)-1-{[(3<i>S</i>)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide
(<b>11a</b>), a compound that showed good κ opioid receptor
antagonist properties. An SAR study based on <b>11a</b> provided
28 novel analogues. Evaluation of these 28 compounds in the [<sup>35</sup>S]GTPγS binding assay showed that several of the analogues
were potent and selective κ opioid receptor antagonists
Identification of 2‑({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)‑1<i>H</i>‑pyrazol-3-yl]carbonyl}amino)tricyclo[3.3.1.13,7]decane-2-carboxylic Acid (NTRC-844) as a Selective Antagonist for the Rat Neurotensin Receptor Type 2
Neurotensin receptor type 2 (NTS2)
compounds display analgesic
activity in animal pain models. We have identified the first high-affinity
NTS2-selective antagonist (<b>8</b>) that is active in vivo.
This study also revealed that the NTS2 FLIPR assay designation for
a compound, agonist, partial agonist, and so forth, did not correlate
with its in vivo activity as observed in the thermal tail-flick acute
model of pain. This suggests that calcium mobilization is not the
signaling pathway involved in NTS2-mediated analgesia as assessed
by the thermal tail-flick model. Finally, we found a significant bias
between rat and human for compound <b>9</b> in the NTS2 binding
assay