Synthesis and In Vitro Opioid Receptor Functional Antagonism of Methyl-Substituted Analogues 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 (JDTic)

Abstract

In previous structure–activity relationship (SAR) studies, (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, 3) was identified as the first potent and selective κ-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a–p of 3 and present their in vitro opioid receptor functional antagonism using a [35S]GTPγS binding assay. Compounds 8a–p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar Ke values at the κ receptor. The three most potent analogues were the monomethylated (3R)-7-hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide (8e) with Ke values of 0.03 nM at the κ receptor and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with Ke=0.037 nM at the κ receptor. All three compounds were selective for the κ receptor relative to the μ and δ receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

“…To assess the validity and generality of the hypothesis that long duration of antagonism was a consequence of JNK activation, we examined the properties of this wide range of available ligands reported to produce selective -opioid antagonism (Portoghese et al, 1987;Carroll et al, 2004Carroll et al, , 2006Cueva et al, 2009;Grimwood et al, 2011). In this analysis, we find that for 12 structurally different -antagonists, stimulation of phospho-JNK-immunoreactivity (ir), in spinal cords of antagonist-injected mice and in KOPr-transfected HEK293 cells treated with antagonist in vitro, is strongly correlated with in vivo duration of antagonism of U50,488-induced analgesia.…”

“…at ASPET Journals on May 13, 2018 molpharm.aspetjournals.org Cueva et al, 2009;Beardsley et al, 2010). The diaryl ethers include FP3FBZ [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide] ; JSPA0658 [(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide] [previously referred to as LY-DMPF (Peters et al, 2011); also known as LY2456302 (Buezo et al, 2010)]; and JSPA071B, [(S)-3-fluoro-4-(4-((2-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide].…”

The Discovery and Development of the N‐Substituted trans‐3,4‐Dimethyl‐4‐(3′‐hydroxyphenyl)piperidine Class of Pure Opioid Receptor Antagonists

“…In a study conducted at RTI, JDTic was found to have K e = 0.02 nM and was 1255- and 3830-fold selective for the κ receptor relative to the μ and δ opioid receptors, respectively (Table 11). [33] For comparison, nor-BNI had K e = 0.04 and 0.05 nM in the OTDP and RTI studies and was 475- and 115-fold (OTDP study) and 520- and 580-fold (RTI study) selective for the κ relative to the μ and δ opioid receptors, respectively. [31, 33] In a study conducted at Lilly Research Laboratories, JDTic had a K e value of 0.098 nM and was 67- and 1718-fold selective for the κ relative to the μ and δ opioid receptors, respectively.…”

“…[33] For comparison, nor-BNI had K e = 0.04 and 0.05 nM in the OTDP and RTI studies and was 475- and 115-fold (OTDP study) and 520- and 580-fold (RTI study) selective for the κ relative to the μ and δ opioid receptors, respectively. [31, 33] In a study conducted at Lilly Research Laboratories, JDTic had a K e value of 0.098 nM and was 67- and 1718-fold selective for the κ relative to the μ and δ opioid receptors, respectively. [34] In comparison, nor-BNI had K e = 0.80 nM and 41-and 18-fold selectivity for the κ relative to the μ and δ opioid receptors, respectively (Table 11).…”

Applications and Modifications of 1,2,3,4-Tetrahydroisoquinoline-3-Carboxylic Acid (Tic) in Peptides and Peptidomimetics Design and Discovery

“…Even though compound 37 possesses druglike properties and performed well in several animal behavioral tests [21][22][23], medicinal chemists still endeavored to pursue analogues which could have better pharmacokinetic properties and ability to penetrate the blood-brain barrier [24][25][26]. Compounds 38-42 were the promising JDTic analogues with ideal calculated logBB which suggested they would possess better blood-brain barrier penetration than compound 37 [26]. Among them, compound 42 was the most potent analogue with K e value of 0.03 nM for the receptor and 120-and 28000-fold selective relative to the μ and opioid receptors.…”