4 research outputs found
4β-Methyl-5-(3-hydroxyphenyl)morphan Opioid Agonist and Partial Agonist Derived from a 4β-Methyl-5-(3-hydroxyphenyl)morphan Pure Antagonist
In
previous studies we reported that addition of 7α-acylamino
groups to <i>N</i>-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan
(<b>4</b>) led to compounds that were pure opioid receptor antagonists.
In contrast to these findings we report in this study that addition
of a 7α-amino (<b>5a</b>), 7α-alkylamino (<b>5b</b>–<b>e</b>), or 7α-dialkylamino (<b>5f</b>–<b>h</b>) group to <b>4</b> leads to
opioid receptor ligands with varying degrees of agonist/antagonist
activity. The 7α-amino and 7α-methylamino analogues were
full agonists at the μ and δ receptors and antagonists
at the κ receptor. The 7α-cyclopropylmethylamino analogue <b>5h</b> was a full agonist at the μ receptor with weaker
agonist activity at the δ and κ receptors. Whereas the
addition of a 7α-acylamino group to the pure nonselective opioid
receptor antagonist <i>N</i>-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan
(<b>4</b>) led to κ selective pure opioid receptor antagonist,
the addition of a 7α-amino, 7α-alkylamino, or 7α-dialkylamino
group to <b>4</b> leads to opioid ligands that are largely μ
or δ agonist with mixed agonist/antagonist properties
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>
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
Discovery of ML314, a Brain Penetrant Nonpeptidic β‑Arrestin Biased Agonist of the Neurotensin NTR1 Receptor
The neurotensin 1 receptor (NTR1) is an important therapeutic target
for a range of disease states including addiction. A high-throughput
screening campaign, followed by medicinal chemistry optimization,
led to the discovery of a nonpeptidic β-arrestin biased agonist
for NTR1. The lead compound, 2-cyclopropyl-6,7-dimethoxy-4-(4-(2-methoxyphenyl)-piperazin-1-yl)quinazoline, <b>32</b> (ML314), exhibits full agonist behavior against NTR1 (EC<sub>50</sub> = 2.0 μM) in the primary assay and selectivity against
NTR2. The effect of <b>32</b> is blocked by the NTR1 antagonist
SR142948A in a dose-dependent manner. Unlike peptide-based NTR1 agonists,
compound <b>32</b> has no significant response in a Ca<sup>2+</sup> mobilization assay and is thus a biased agonist that activates the
β-arrestin pathway rather than the traditional G<sub><i>q</i></sub> coupled pathway. This bias has distinct biochemical
and functional consequences that may lead to physiological advantages.
Compound <b>32</b> displays good brain penetration in rodents,
and studies examining its in vivo properties are underway