5 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]ÂCP55,940, 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
Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6‑Pyrrolidinylpyridinyl Substitution
Allosteric
modulators of the cannabinoid CB1 receptor have recently been reported
as an alternative approach to modulate the CB1 receptor for therapeutic
benefits. In this study, we report the design and synthesis of a series
of diarylureas derived from PSNCBAM-1 (<b>2</b>). Similar to <b>2</b>, these diarylureas dose-dependently inhibited CP55,940-induced
intracellular calcium mobilization and [<sup>35</sup>S]ÂGTP-γ-S
binding while enhancing [<sup>3</sup>H]ÂCP55,940 binding to the CB1
receptor. Structure–activity relationship studies revealed
that the pyridinyl ring of <b>2</b> could be replaced by other
aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric
modulation. <b>34</b> (RTICBM-74) had similar potencies as <b>2</b> in all in vitro assays but showed significantly improved
metabolic stability to rat liver microsomes. More importantly, <b>34</b> was more effective than <b>2</b> in attenuating the
reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating
the potential of this diarylurea series as promising candidates for
the development of relapse treatment of cocaine addiction
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