JDTic

JDTic
Clinical data
Other names	JDTic
Identifiers
	IUPAC name (3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
CAS Number	361444-66-8 ;
PubChem CID	9956146;
IUPHAR/BPS	7362;
ChemSpider	8131755 ;
UNII	3C6FZ6UXC8;
PDB ligand	JDC (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID70433301 ;
Chemical and physical data
Formula	C28H39N3O3
Molar mass	465.638 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@H]1CN(CC[C@@]1(C)C2=CC(=CC=C2)O)C[C@H](C(C)C)NC(=O)[C@H]3CC4=C(CN3)C=C(C=C4)O;
	InChI InChI=1S/C28H39N3O3/c1-18(2)26(30-27(34)25-13-20-8-9-24(33)12-21(20)15-29-25)17-31-11-10-28(4,19(3)16-31)22-6-5-7-23(32)14-22/h5-9,12,14,18-19,25-26,29,32-33H,10-11,13,15-17H2,1-4H3,(H,30,34)/t19-,25+,26+,28+/m0/s1 ; Key:ZLVXBBHTMQJRSX-VMGNSXQWSA-N ;
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JDTic is a selective, long-acting ("inactivating") antagonist of the κ-opioid receptor (KOR).^[1]^[2] JDTic is a 4-phenylpiperidine derivative, distantly related structurally to analgesics such as pethidine and ketobemidone, and more closely to the MOR antagonist alvimopan. In addition, it is structurally distinct from other KOR antagonists such as norbinaltorphimine.^[3]^[4] JDTic has been used to create crystal structures of KOR [ PDB: 4DJH, 6VI4].^[5]^[6]

^ Thomas JB, Atkinson RN, Rothman RB, Fix SE, Mascarella SW, Vinson NA, Xu H, Dersch CM, Lu Y, Cantrell BE, Zimmerman DM, Carroll FI (2001). "Identification of the First trans-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine Derivative to Possess Highly Potent and Selective Opioid κ Receptor Antagonist Activity". Journal of Medicinal Chemistry. 44 (17): 2687–2690. doi:10.1021/jm015521r. PMID 11495579.
^ Zaveri NT, Journigan VB, Polgar WE (2015). "Discovery of the First Small-Molecule Opioid Pan Antagonist with Nanomolar Affinity at Mu, Delta, Kappa, and Nociceptin Opioid Receptors". ACS Chem Neurosci. 6 (4): 646–57. doi:10.1021/cn500367b. PMC 4401318. PMID 25635572.
^ Thomas JB, Atkinson RN, Vinson NA, Catanzaro JL, Perretta CL, Fix SE, Mascarella SW, Rothman RB, Xu H, Dersch CM, Cantrell BE, Zimmerman DM, Carroll FI (2003). "Identification of (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 as a Novel Potent and Selective Opioid κ Receptor Antagonist". Journal of Medicinal Chemistry. 46 (14): 3127–3137. doi:10.1021/jm030094y. PMID 12825951.
^ Cai TB, Zou Z, Thomas JB, Brieaddy L, Navarro HA, Carroll FI (2008). "Synthesis and in vitro Opioid Receptor Functional Antagonism of Analogues of the Selective κ Opioid Receptor Antagonist (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 (JDTic)". Journal of Medicinal Chemistry. 51 (6): 1849–1860. doi:10.1021/jm701344b. PMID 18307295.
^ Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012). "Structure of the Human κ-Opioid Receptor in Complex with JDTic". Nature. 485 (7398): 327–332. Bibcode:2012Natur.485..327W. doi:10.1038/nature10939. PMC 3356457. PMID 22437504.
^ Che T, English J, Krumm BE, Kim K, Pardon E, Olsen RH, et al. (March 2020). "Nanobody-enabled monitoring of kappa opioid receptor states". Nature Communications. 11 (1): 1145. Bibcode:2020NatCo..11.1145C. doi:10.1038/s41467-020-14889-7. PMC 7052193. PMID 32123179.

[pmid11495579-1] Thomas JB, Atkinson RN, Rothman RB, Fix SE, Mascarella SW, Vinson NA, Xu H, Dersch CM, Lu Y, Cantrell BE, Zimmerman DM, Carroll FI (2001). "Identification of the First trans-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine Derivative to Possess Highly Potent and Selective Opioid κ Receptor Antagonist Activity". Journal of Medicinal Chemistry. 44 (17): 2687–2690. doi:10.1021/jm015521r. PMID 11495579.

[pmid25635572-2] Zaveri NT, Journigan VB, Polgar WE (2015). "Discovery of the First Small-Molecule Opioid Pan Antagonist with Nanomolar Affinity at Mu, Delta, Kappa, and Nociceptin Opioid Receptors". ACS Chem Neurosci. 6 (4): 646–57. doi:10.1021/cn500367b. PMC 4401318. PMID 25635572.

[3] Thomas JB, Atkinson RN, Vinson NA, Catanzaro JL, Perretta CL, Fix SE, Mascarella SW, Rothman RB, Xu H, Dersch CM, Cantrell BE, Zimmerman DM, Carroll FI (2003). "Identification of (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 as a Novel Potent and Selective Opioid κ Receptor Antagonist". Journal of Medicinal Chemistry. 46 (14): 3127–3137. doi:10.1021/jm030094y. PMID 12825951.

[4] Cai TB, Zou Z, Thomas JB, Brieaddy L, Navarro HA, Carroll FI (2008). "Synthesis and in vitro Opioid Receptor Functional Antagonism of Analogues of the Selective κ Opioid Receptor Antagonist (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 (JDTic)". Journal of Medicinal Chemistry. 51 (6): 1849–1860. doi:10.1021/jm701344b. PMID 18307295.

[5] Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012). "Structure of the Human κ-Opioid Receptor in Complex with JDTic". Nature. 485 (7398): 327–332. Bibcode:2012Natur.485..327W. doi:10.1038/nature10939. PMC 3356457. PMID 22437504.

[6] Che T, English J, Krumm BE, Kim K, Pardon E, Olsen RH, et al. (March 2020). "Nanobody-enabled monitoring of kappa opioid receptor states". Nature Communications. 11 (1): 1145. Bibcode:2020NatCo..11.1145C. doi:10.1038/s41467-020-14889-7. PMC 7052193. PMID 32123179.

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