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Discovery of the first small-molecule opioid pan antagonist with nanomolar affinity at mu, delta, kappa, and nociceptin opioid receptors.

Zaveri NT, Journigan VB, Polgar WE - ACS Chem Neurosci (2015)

Bottom Line: When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic.AT-076 is the first opioid pan antagonist with high affinity at all four opioid receptor subtypes.Our SAR studies show that the 3,4-dimethyl groups of the well-known trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist scaffold may be removed without significant loss in binding affinity or antagonist potency to obtain an opioid pan antagonist such as AT-076.

View Article: PubMed Central - PubMed

Affiliation: †Astraea Therapeutics, 320 Logue Avenue, Suite 142, Mountain View, California 94043, United States.

ABSTRACT
The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine scaffold is a known pharmacophore for mu opioid (MOP), kappa opioid (KOP), and delta opioid (DOP) receptor antagonists; however, it has not been explored in nociceptin opioid (NOP/ORL-1) receptor ligands. We recently found that the selective KOP antagonist JDTic, (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide, containing this opioid antagonist pharmacophore, has significant binding affinity at the NOP receptor (Ki 16.67 ± 0.76 nM), with no intrinsic activity in the [(35)S]GTPγS functional assay. Since this is the first ligand containing the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist pharmacophore to have affinity for the NOP receptor, we explored the structural determinants of its NOP binding affinity. When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic. Interestingly, however, removal of the 3,4-dimethyl groups of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine antagonist scaffold of JDTic increased the binding affinity at NOP by 10-fold (Ki 1.75 ± 0.74 nM) while maintaining comparable affinity for KOP, MOP, and DOP receptors (Ki 1.14 ± 0.63, 1.67 ± 0.6, and 19.6 ± 1.3 nM, respectively). In vitro functional efficacy studies using the [(35)S]GTPγS assay showed that this compound AT-076 functions as an antagonist at all four opioid receptors. Detailed characterization of the antagonist activity of AT-076 shows that it has a noncompetitive antagonist profile at the NOP and KOP receptors (insurmountable antagonism), but is a potent competitive antagonist at the MOP and DOP receptors, with Ke values 3-6-fold more potent than those of JDTic. AT-076 is the first opioid pan antagonist with high affinity at all four opioid receptor subtypes. Our SAR studies show that the 3,4-dimethyl groups of the well-known trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist scaffold may be removed without significant loss in binding affinity or antagonist potency to obtain an opioid pan antagonist such as AT-076.

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Structures of trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine-containingopioidantagonists and phenylpiperidine-containing opioid and nociceptinreceptor ligands. (a) From ref (6). (b) From ref (7).
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fig1: Structures of trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine-containingopioidantagonists and phenylpiperidine-containing opioid and nociceptinreceptor ligands. (a) From ref (6). (b) From ref (7).

Mentions: The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidinescaffold is a known opioid antagonist pharmacophore for the mu, delta,and kappa opioid receptors (MOP, KOP, and DOP, respectively),1 and is present in several opioid antagonistssuch as the nonselective opioid antagonist LY255582,2 the peripherally restricted mu opioid antagonist LY246736(Alvimopan; ENTEREG),3 and the kappa opioidantagonist JDTic4 (Figure 1). However, this universal opioid antagonist pharmacophorehas not been explored for antagonists at the fourth opioid subtype,nociceptin opioid receptor (NOP). Although opioid peptides and classicalmorphinan-based opioid ligands do not have appreciable affinity forNOP, phenylpiperidine-type scaffolds are found among both opioid (e.g.,fentanyl, lofentanil) as well as NOP ligands (e.g., SB-612111) (Figure 1). As part of our continuing investigation intonovel NOP ligands, we examined the affinity of the kappa opioid antagonistJDTic at the NOP receptor, and found it to have surprisingly highaffinity at NOP, with a Ki of 16.7 ±0.76 nM and no intrinsic activity in the [35S]GTPγSfunctional assay, in agreement with a recent report by Munro and colleagues5 (Table 1). Since thiswas the first trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine-containing ligandto show good binding affinity at the NOP receptor, we explored thestructural determinants of JDTic’s NOP binding affinity andfunctional activity, with rational chemical modifications designedto inform the structure–activity relationship (SAR) of thevarious functionalities of this new ‘antagonist’ moleculeat the NOP receptor. The chemical modifications explored are shownin Figure 2.


Discovery of the first small-molecule opioid pan antagonist with nanomolar affinity at mu, delta, kappa, and nociceptin opioid receptors.

Zaveri NT, Journigan VB, Polgar WE - ACS Chem Neurosci (2015)

Structures of trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine-containingopioidantagonists and phenylpiperidine-containing opioid and nociceptinreceptor ligands. (a) From ref (6). (b) From ref (7).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401318&req=5

fig1: Structures of trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine-containingopioidantagonists and phenylpiperidine-containing opioid and nociceptinreceptor ligands. (a) From ref (6). (b) From ref (7).
Mentions: The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidinescaffold is a known opioid antagonist pharmacophore for the mu, delta,and kappa opioid receptors (MOP, KOP, and DOP, respectively),1 and is present in several opioid antagonistssuch as the nonselective opioid antagonist LY255582,2 the peripherally restricted mu opioid antagonist LY246736(Alvimopan; ENTEREG),3 and the kappa opioidantagonist JDTic4 (Figure 1). However, this universal opioid antagonist pharmacophorehas not been explored for antagonists at the fourth opioid subtype,nociceptin opioid receptor (NOP). Although opioid peptides and classicalmorphinan-based opioid ligands do not have appreciable affinity forNOP, phenylpiperidine-type scaffolds are found among both opioid (e.g.,fentanyl, lofentanil) as well as NOP ligands (e.g., SB-612111) (Figure 1). As part of our continuing investigation intonovel NOP ligands, we examined the affinity of the kappa opioid antagonistJDTic at the NOP receptor, and found it to have surprisingly highaffinity at NOP, with a Ki of 16.7 ±0.76 nM and no intrinsic activity in the [35S]GTPγSfunctional assay, in agreement with a recent report by Munro and colleagues5 (Table 1). Since thiswas the first trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine-containing ligandto show good binding affinity at the NOP receptor, we explored thestructural determinants of JDTic’s NOP binding affinity andfunctional activity, with rational chemical modifications designedto inform the structure–activity relationship (SAR) of thevarious functionalities of this new ‘antagonist’ moleculeat the NOP receptor. The chemical modifications explored are shownin Figure 2.

Bottom Line: When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic.AT-076 is the first opioid pan antagonist with high affinity at all four opioid receptor subtypes.Our SAR studies show that the 3,4-dimethyl groups of the well-known trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist scaffold may be removed without significant loss in binding affinity or antagonist potency to obtain an opioid pan antagonist such as AT-076.

View Article: PubMed Central - PubMed

Affiliation: †Astraea Therapeutics, 320 Logue Avenue, Suite 142, Mountain View, California 94043, United States.

ABSTRACT
The trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine scaffold is a known pharmacophore for mu opioid (MOP), kappa opioid (KOP), and delta opioid (DOP) receptor antagonists; however, it has not been explored in nociceptin opioid (NOP/ORL-1) receptor ligands. We recently found that the selective KOP antagonist JDTic, (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide, containing this opioid antagonist pharmacophore, has significant binding affinity at the NOP receptor (Ki 16.67 ± 0.76 nM), with no intrinsic activity in the [(35)S]GTPγS functional assay. Since this is the first ligand containing the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist pharmacophore to have affinity for the NOP receptor, we explored the structural determinants of its NOP binding affinity. When rational chemical modifications of JDTic were carried out, based on our previously established NOP pharmacophoric structure-activity relationship (SAR) model, most modifications led to a significant decrease in NOP and opioid binding affinity compared to JDTic. Interestingly, however, removal of the 3,4-dimethyl groups of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine antagonist scaffold of JDTic increased the binding affinity at NOP by 10-fold (Ki 1.75 ± 0.74 nM) while maintaining comparable affinity for KOP, MOP, and DOP receptors (Ki 1.14 ± 0.63, 1.67 ± 0.6, and 19.6 ± 1.3 nM, respectively). In vitro functional efficacy studies using the [(35)S]GTPγS assay showed that this compound AT-076 functions as an antagonist at all four opioid receptors. Detailed characterization of the antagonist activity of AT-076 shows that it has a noncompetitive antagonist profile at the NOP and KOP receptors (insurmountable antagonism), but is a potent competitive antagonist at the MOP and DOP receptors, with Ke values 3-6-fold more potent than those of JDTic. AT-076 is the first opioid pan antagonist with high affinity at all four opioid receptor subtypes. Our SAR studies show that the 3,4-dimethyl groups of the well-known trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist scaffold may be removed without significant loss in binding affinity or antagonist potency to obtain an opioid pan antagonist such as AT-076.

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