Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives

We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of the N-substituent on the functional activities because the side chain and S=O part in the sulfonamide moiety located in spatially different positions compared with those in the alkylamine and amide moieties. Among the tested compounds, cyclopropylsulfonamide 9f (SYK-839) was the most potent full inverse agonist for the DOR, whereas phenethylsulfonamide 9e (SYK-901) showed full DOR agonist activity with moderate potency. These NTI derivatives are expected to be useful compounds for investigation of the molecular mechanism inducing these functional activities.

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δ Opioid Receptor Inverse Agonists and their In Vivo Pharmacological Effects

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200402115654 ◽

2020 ◽

Vol 20 (31) ◽

pp. 2889-2902 ◽

Cited By ~ 1

Author(s):

Shigeto Hirayama ◽

Hideaki Fujii

Keyword(s):

Opioid Receptor ◽

Short Term Memory ◽

Inverse Agonist ◽

Pharmacological Effects ◽

Short Term ◽

Inverse Agonists ◽

Δ Opioid Receptor ◽

Receptor Inverse Agonist

The discovery of δ opioid receptor inverse agonist activity induced by ICI-174,864, which was previously reported as an δ opioid receptor antagonist, opened the door for the investigation of inverse agonism/constitutive activity of the receptors. Various peptidic or non-peptidic δ opioid receptor inverse agonists have since been developed. Compared with the reports dealing with in vitro inverse agonist activities of novel compounds or known compounds as antagonists, there have been almost no publications describing the in vivo pharmacological effects induced by a δ opioid receptor inverse agonist. After the observation of anorectic effects with the δ opioid receptor antagonism was discussed in the early 2000s, the short-term memory improving effects and antitussive effects have been very recently reported as possible pharmacological effects induced by a δ opioid receptor inverse agonist. In this review, we will survey the developed δ opioid receptor inverse agonists and summarize the possible in vivo pharmacological effects by δ opioid receptor inverse agonists. Moreover, we will discuss important issues involved in the investigation of the in vivo pharmacological effects produced by a δ opioid receptor inverse agonist.

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Analogues of cholecystokinin 26–33 selective for B-type CCK receptors possess δ opioid receptor agonist activity in vitro and in vivo: Evidence for similarities in CCK-B and δ opioid receptor requirements

Peptides ◽

10.1007/978-94-011-0683-2_221 ◽

1994 ◽

pp. 669-671 ◽

Cited By ~ 3

Author(s):

V. J. Hruby ◽

S. N. Fang ◽

T. H. Kramer ◽

P. Davis ◽

D. Parkhurst ◽

...

Keyword(s):

Opioid Receptor ◽

Receptor Agonist ◽

Agonist Activity ◽

Cck Receptors ◽

Opioid Receptor Agonist ◽

Δ Opioid Receptor

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Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00368 ◽

2019 ◽

Vol 10 (9) ◽

pp. 3939-3945 ◽

Cited By ~ 1

Author(s):

Eika Higashi ◽

Shigeto Hirayama ◽

Jun Nikaido ◽

Marie Shibasaki ◽

Tomomi Kono ◽

...

Keyword(s):

Nitrogen Atom ◽

Opioid Receptor ◽

Inverse Agonists ◽

Basic Nitrogen ◽

Δ Opioid Receptor

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(2S,3R)TMT-l-Tic-OH is a potent inverse agonist at the human δ-opioid receptor

European Journal of Pharmacology ◽

10.1016/s0014-2999(99)00516-6 ◽

1999 ◽

Vol 380 (1) ◽

pp. R9-R10 ◽

Cited By ~ 15

Author(s):

Keiko Hosohata ◽

Thomas H Burkey ◽

Josua Alfaro-Lopez ◽

Victor J Hruby ◽

William R Roeske ◽

...

Keyword(s):

Opioid Receptor ◽

Inverse Agonist ◽

Δ Opioid Receptor

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κ- and δ-opioid receptor functional activities are increased in the caudate putamen of cannabinoid CB1receptor knockout mice

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2005.04372.x ◽

2005 ◽

Vol 22 (8) ◽

pp. 2106-2110 ◽

Cited By ~ 21

Author(s):

Leyre Urigüen ◽

Fernando Berrendero ◽

Catherine Ledent ◽

Rafael Maldonado ◽

Jorge Manzanares

Keyword(s):

Opioid Receptor ◽

Knockout Mice ◽

Caudate Putamen ◽

Functional Activities ◽

Δ Opioid Receptor

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Molecular Mechanism of Action of RORγt Agonists and Inverse Agonists: Insights from Molecular Dynamics Simulation

Molecules ◽

10.3390/molecules23123181 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3181 ◽

Cited By ~ 10

Author(s):

Nannan Sun ◽

Congmin Yuan ◽

Xiaojun Ma ◽

Yonghui Wang ◽

Xianfeng Gu ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Mechanism ◽

Mechanism Of Action ◽

Critical Role ◽

Inverse Agonist ◽

Orphan Receptor ◽

Dynamics Simulation ◽

Side Chain ◽

Trans Conformation ◽

Molecular Mechanism Of Action

As an attractive drug-target, retinoic acid receptor-related orphan receptor-gamma-t (RORγt) has been employed widely to develop clinically relevant small molecular modulators as potent therapy for autoimmune disease and cancer, but its molecular mechanism of action (MOA) remains unclear. In the present study, we designed and discovered two novel RORγt ligands that are similar in structure, but different in efficacy. Using fluorescence resonance energy transfer (FRET) assay, compound 1 was identified as an agonist with an EC50 of 3.7 μM (max. act.: 78%), while compound 2 as an inverse agonist with an IC50 value of 2.0 μM (max. inh.: 61%). We performed molecular dynamics (MD) simulations, and elucidated the MOA of RORγt agonist and inverse agonist. Through the analyses of our MD results, we found that, after RORγt is bound with the agonist 1, the side chain of Trp317 stays in the gauche- conformation, and thus helps to form the hydrogen bond, His479-Trp502, and a large hydrophobic network among H11, H11′, and H12. All these interactions stabilize the H12, and helps the receptor recruit the coactivator. When the RORγt is bound with the inverse agonist 2, the side chain of Trp317 is forced to adopt the trans conformation, and these presumed interactions are partially destroyed. Taken together, the critical role of residue Trp317 could be viewed as the driving force for the activation of RORγt.

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