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 kappa-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 [(35)S]GTPgammaS 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 K(e) values at the kappa 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 K(e) values of 0.03 nM at the kappa 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 K(e) = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the micro and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.

Figure 1

Scheme 1^a

^a Reagents: (a) BOP, THF, Et₃N (for 8d, 8f–g, 8i–l, 8n–p), or HBTU, CH₃CN, Et₃N, (for 8e, 8h, 8m) for coupling with 6a and 6c; (b) CF₃CO₂H, CH₂Cl₂; (c) Raney Ni, H₂, HCHO, CH₃OH.

Scheme 2^a

^a Reagents: (a) NaOH, C₆H₅CHO; (b) C₆H₅COCl; (c) LiHMDS, THF, −78 °C; CH₃OC₆H₄CH₂Br; (d) conc HCl; (e) Br₂, HCl; (f) HCHO, HBr, H₂O, CF₃CO₂H; (g) conc HBr, reflux; (h) H₂, Pd/C, CH₃OH; (i) (Boc)₂O, DMF, Et₃N; (j) CF₃CO₂H, CH₂Cl₂; (k) Raney Ni, H₂, CH₃OH, HCHO; (l) 12 M HCl, THF.

Scheme 3^a

^a Reagents: (a) N-Boc-L-valine, BOP, THF; (b) N-Boc-L-isoleucine, HBTU, CH₃CN, Et₃N, THF; (c) B₂H₆, THF.