Synthesis and In Vitro Opioid Receptor Functional Antagonism of Analogues of the Selective Kappa 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)

Abstract

In previous structure-activity relationship (SAR) studies, we identified (3 R)-7-hydroxy- N-((1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 1) as the first potent and selective kappa opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [ (35) S]GTPgammaS binding assay. The results from the studies better define the pharmacophore for this class of kappa opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3 R)-7-Hydroxy- N-[(1 S,2 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide ( 3) with a K e value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified.

Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: In Vitro Pharmacology and ADME Profile

“…33 The nitro ( 41 ), acetylamino ( 42 ), methanesulfonylamino ( 43 ), and amino ( 44 ) analogues were 320-, 70-, 200-, and 10-times less potent as a κ antagonist than JDTic and were not as selective for the κ receptor relative to the μ and δ receptors as JDTic. The methoxy ( 45 ) analogue was only 3-fold less potent than JDTic as a κ antagonist.…”

“…In previous studies, we reported that 37 , which has a carboxamide group replacing the hydroxyl of the 4-(3-hydroxyphenyl) group, has a K e = 0.12 nM at the κ receptor, which was only 6 times less potent than JDTic as a κ opioid receptor (KOR) antagonist (Table 2). 33 …”

“…These molecular descriptors were calculated for JDTic, previously reported 37 , 33 as well as 4 , 5 , 13 , and 14 (Table 3). In general, CNS drugs have clogP in the range 2–4, 45 TPSA less than 76 Å 2 , 46 and logBB greater than −1.…”

“…32 Careful hydrolysis of the methyl ester using lithium hydroxide in aqueous dioxane, followed by addition of hydrogen peroxide to the cooled solution, resulted in a very rapid hydrolysis of the benzonitrile to the benzamide 36 . The appropriate amine ( 21 , 3-{(3 R ,4 R )-1-[(2 S )-2-amino-3-methylbutyl]-3,4-dimethylpiperidin-4-yl}benzamide, 33 or 20 ) could then be coupled with 36 using HBTU or EDC·HCl to afford the intermediate amides which yielded the desired compounds 13 , 14 , and 15 upon deprotection of the Boc group with trifluoroacetic acid in dichloromethane or hydrochloric acid in aqueous methanol.…”

Synthesis and Screening of C1‐Substituted Tetrahydroisoquinoline Derivatives for Asymmetric Transfer Hydrogenation Reactions

“…This was achieved by refluxing the compound in acetone in the presence of Me 2 SO 4 and KHCO 3 . [21] The crude product was purified using column chromatography to obtain the desired compound 12 in a 80 % yield. Afterwards, deprotection of the Cbz group of 12 was accomplished and subsequent reduction to the amino alcohol afforded 14 (Scheme 3).…”