Synthesis and Pharmacological Evaluation of Novel C-8 Substituted Tetrahydroquinolines as Balanced-Affinity Mu/Delta Opioid Ligands for the Treatment of Pain

Abstract

The use of opioids for the treatment of pain, while largely effective, is limited by detrimental side effects including analgesic tolerance, physical dependence, and euphoria, which may lead to opioid abuse. Studies have shown that compounds with a μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist profile reduce or eliminate some of these side effects including the development of tolerance and dependence. Herein we report the synthesis and pharmacological evaluation of a series of tetrahydroquinoline-based peptidomimetics with substitutions at the C-8 position. Relative to our lead peptidomimetic with no C-8 substitution, this series affords an increase in DOR affinity and provides greater balance in MOR and DOR binding affinities. Moreover, compounds with carbonyl moieties at C-8 display the desired MOR agonist/DOR antagonist profile whereas alkyl substitutions elicit modest DOR agonism. Several compounds in this series produce a robust antinociceptive effect in vivo and show antinociceptive activity for greater than 2 h after intraperitoneal administration in mice.

Keywords: Bifunctional ligands; dependence; drug abuse; opioids; peptidomimetics; tolerance.

Figure 1.

Lead peptidomimetic 1, featuring the THQ core and numbering convention in blue. Current SAR exploration focuses on substitutions at C-8.

Scheme 1^a

^a(i) 3-Bromopropionyl chloride, K₂CO₃. (ii) NaOtBu. (iii) TfOH. (iv) NBS. (v) see Scheme 2. (vi) benzyl (5a–k) or phenethyl (5l) boronic acid, Pd(dppf)Cl₂, K₂CO₃. (vii, viii) see Schemes 3 and 4.

Scheme 2^a

^a(iii) TfOH. (iv) NBS. (v) TFAA. (v′) NBS, benzoyl peroxide (v″) amine, K₂CO₃.

Scheme 3^a

^a(vii) CO, Pd(dppf)Cl₂, MeOH (5n) or H₂O (4a′).

Scheme 4^a

^a(viii) Amine, PyBOP, DIPEA.

Scheme 5^a

^a(ix) (R)-(+)-2-methyl-2-propanesulfinamide, then NaBH₄. (x) HCl, then diBocDmt, PyBOP, 6-Cl HOBt, DIPEA, then TFA. (xi) LiOH (prior to TFA deprotection).