Synthesis, Molecular Pharmacology, and Structure-Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists

Abstract

Synthetic indole cannabinoids characterized by a 2',2'-dimethylindan-5'-oyl group at the indole C3 position constitute a new class of ligands possessing high affinity for human CB₂ receptors at a nanomolar concentration and a good selectivity index. Starting from the neutral antagonist 4, the effects of indole core modification on the pharmacodynamic profile of the ligands were investigated. Several N1 side chains afforded potent and CB₂-selective neutral antagonists, notably derivatives 26 (R¹ = n-propyl, R² = H) and 35 (R¹ = 4-pentynyl, R² = H). Addition of a methyl group at C2 improved the selectivity for the CB₂ receptor. Moreover, C2 indole substitution may control the CB₂ activity as shown by the functionality switch in 35 (antagonist) and 49 (R¹ = 4-pentynyl, R² = CH₃, partial agonist).

Figure 1.

Rational design of a novel class of potent cannabinoids.

Figure 2.

Affinities (K_i) of selected derivatives for hCB₁ and hCB₂ receptors.

Figure 3.

Binding modes of selected derivatives in CB₁ (A1–F1) and CB₂ (A2–F2) receptors. (A1) GBD-002 (3), CB₁; (A2) GBD-002 (3), CB₂; (B1) GBD-003 (4), CB₁; (B2) GBD-003 (4), CB₂; (C1) GBD-005 (26), CB₁; (C2) GBD-005 (26), CB₂; (D1) GBD-013 (34), CB₁; (D2) GBD-013 (34), CB₂; (E1) GBD-014 (35), CB₁; (E2) GBD-014 (35), CB₂; (F1) GBD-029 (49), CB₁; (F2) GBD-029 (49), CB₂. Original crystal structures of CB₁R (5XR8) and CB₂R (5ZTY) were obtained from the Protein Data Bank for modeling. Pivotal to the difference in binding modes of these compounds between CB₁R and CB₂R are the residue changes L193/I110 and L481/V261 (in CB₁R and CB₂R, respectively). These substitutions allow for the central indole scaffold of the GBD compounds to rotate, allowing for the dimethylindane moiety and its connecting ketone to engage in hydrogen bonding with S285. Modifications to the aliphatic chain such as truncation (C1-2) and dehydrogenation (D1-2, E1-2) reduce hydrophobic interactions with the nearby hydrophobic pockets in CB₁R and CB₂R. The resulting indole moiety rotation due to the residue changes between CB₁R and CB₂R also allows for substitutions (F1–F2) on the indole moiety with CB2R that are otherwise unavailable in CB₁R.

Figure 4.

GBD-003 acts as an antagonist at CHO-hCB2 receptors, producing concentration-dependent reduction of G-protein activation produced by the hCB2 receptor agonist CP-55,940.

Scheme 1.. Synthesis of JWH-018^a

^aReagents and conditions: (a) MeMgBr, Et₂O/THF, 0 °C, then 1-naphthoyl Cl, reflux. (b) n-Pentyl Cl, KOH, DMSO, 80 °C.

Scheme 2.. Overview of the Synthetic Approach

Scheme 3.. Synthesis of Benzoate 10, the Precursor to 3-(Indan-4-oyl)indole GBD-002^a

^aReagents and conditions: (a) 2-fluorobenzyl bromide, LDA, THF, −78 °C to rt, 5 h, 81%. (b) DIBAL-H, THF, −78 °C to rt, 1 h, 88%. (c) MsCl, Et₃N, CH₂Cl₂, 0 °C, 1 h, 91%. (d) NaI, NMP, 140 °C, 8 h, 89%. (e) (i) t-BuLi, n-pentane-Et₂O (4:1 by vol), −78 °C, 15 min; (ii) THF, −78 °C; (iii) −78 °C to rt to −78 °C; (iv) ClCO₂Et, −78 °C (15 min) to rt (15 min).

Scheme 4.. Synthesis of the 3-(Indan-4-oyl)indole GBD-002^a

^aReagents and conditions: (a) Tf₂O, pyridine, CH₂Cl₂, −78 °C to rt, 20 min, 97%. (b) (i) lithio ethyl acetate, THF, −78 °C, 20 min; (ii) LHMDS, 0 °C (10 min) to rt (1 h), 63%. (c) Tf₂O, aq. LiOH, hexanes, 0 °C to rt, 30 min, 88%. (d) LHMDS, THF, 0 °C to rt, 1 h, 63%. (e) (i) [Rh(cod)₂]BF₄, (±)-BINAP, H₂, CH₂Cl₂, rt, 1 h; (ii) TMS-acetylene, CH₂Cl₂, rt, 1 h, 90%. (f) KI, TMSCl, H₂O, CH₃CN, 60 °C, 12 h, 68%. (g) KOH, H₂O, EtOH, rt, 8 h, 95%. (h) (i) SOCl₂, DMF, CH₂Cl₂, rt, 8 h; (ii) N-pentylindole, HFIP, rt, 24 h, 68%.

Scheme 5.. Synthesis of 3-(Indan-5-oyl)indoles^a

^aReagents and conditions: (a) Tf₂O, pyridine, CH₂Cl₂, −78 °C to rt, 20 min, 97%. (b) DIBAL-H, THF, −78 °C, 1–2 h, 90%. (c) Ethyl-E-4-(diethoxyphosphoryl)but-2-enoate, LHMDS, THF, −78 °C (15 min) to rt to 60 °C (1 h), 82%. (d) (i) [Rh(nbd)Cl]₂, AgSbF₆, CH₂Cl₂, rt, 1 h; (ii) DDQ, rt, 2 h, 85%. (e) KOH, H₂O, EtOH, rt, 8 h, 96%. (f) (i) SOCl₂, DMF, CH₂Cl₂, rt, 8 h; (ii) indole or 2-methylindole, HFIP, rt, 24 h, 53–58%. (g) Alkyl halide, NaH, DMSO, rt, 8 h.