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 (EC₅₀ = 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 Ca²⁺ mobilization assay and is thus a biased agonist that activates the β-arrestin pathway rather than the traditional G_<i>q</i> 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