Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues

Abstract

In pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action, we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1'-substituents, carries a metabolically labile 2',3'-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and non-human primates. The lead molecule identified here, namely, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), was found to exhibit remarkably high in vitro and in vivo potency with shorter duration of action than the currently existing classical cannabinoid agonists.

Figure 1

Design of the first and second generation side chain carboxylated cannabinoid analogues, with controllable deactivation and increasing polarity, and structures of the prototype (−)-Δ⁸-THC-DMH and inactive metabolites.

Figure 2

Effects of 3a, 3b, and 3c, 11-OH-Δ⁸-THC-DMH (3g), or vehicle (left-most points, above Veh) on rectal body temperature using female Sprague-Dawley rats (n = 6). Abscissa: dose, in mg/kg. Ordinate: change in rectal body temperature from an average baseline of 38.1 ± 0.3 °C. Symbols represent the average (±SEM; n = 6 except 1.0 mg/kg 3b, for which n = 3) of individual peak effects measured within 6 h of injection. Actual time varied with dose and compound. Solid symbols indicate effects that are significantly different from vehicle.

Figure 3

Hypothermic effects of select doses of 3a, 3b, 11-OH-Δ⁸-THC-DMH (3g), and 3c at different times after injection. The doses selected were the lowest doses that decreased temperature by ≥4 °C in female Sprague–Dawley rats (n = 6). The dotted line represents temperature changes after vehicle injection. Abscissa: time (in min) after injection. Ordinate; change in body temperature. Filled symbols indicate effects that are significantly different from vehicle.

Figure 4

Tail-flick latencies in a hot water-bath (52 °C) after administration of two doses each of compounds 3b and 3g at four time-points (20, 60, 180, and 360 min postadministration) using male CD-1 mice (n = 6). Abscissa: time (min) after injection. Ordinate; tailflick withdrawal latencies expressed as a percentage of maximum possible effect (% MPE; group mean ± SEM).

Figure 5

Time course of CB1 discriminative-stimulus effects of 3b (0.001 mg/kg) and 3g (0.003 mg/kg).

Scheme 1^a

^aReagents and conditions: (a) MeI, K₂CO₃, acetone, rt, overnight, 72%; (b) BBr₃, CH₂Cl₂, −78 to 0 °C, 2.5 h, 71%; (c) 6, BF₃·Et₂O, CH₂Cl₂, −20 °C to rt, 2 h, 40%; (d) NaOH, THF/H₂O, reflux, 12 h 68%; (e) Br(CH₂)₃CH₃, NaHCO₃, DMF, microwave irradiation, 165 °C, 12 min, 51%.

Scheme 2^a

^aReagents and conditions: (a) BBr₃, CH₂Cl₂, 0 °C to rt, 3.5 h, 98%; (b) NaHCO₃, 1-bromobutane, DMF, 165 °C, microwave irradiation, 12 min, 92%; (c) 14, p-TSA, CHCl₃, 0 °C to rt, 4 days, 27%; (d) TMSOTf, CH₂Cl₂/MeNO₂, 0 °C to rt, 7 h, 67%; (e) TBDMSCl, imidazole, DMAP, DMF, rt, 12 h, 87%; (f) Cl⁻Ph₃P⁺CH₂OMe, Na tert-amylate, benzene, 0 °C to rt, 3 h, 63%; (g) CCl₃COOH, H₂O, CH₂Cl₂, rt, 1 h, 97%; (h) K₂CO₃, EtOH, rt, 3 h, 78%; (i) NaBH₄, EtOH, rt, 30 min, 85%; (j) TBAF, THF, −40 °C, 30 min, 90%; (k) LiOH, dioxane/H₂O, rt, 24 h, 85%.

Scheme 3^a

^aReagents and conditions: (a) NaBH₄, MeOH, −78 °C, 2 h, 84%; (b) LiOH, dioxane/H₂O, rt, 24 h, 63%; (c) NaBH₄, MeOH, rt, 1 h, 81%; (d) K-selectride, THF, rt, 2 h, 91%; (e) NaHCO₃, 1-bromobutane, DMF, 165 °C, microwave irradiation, 12 min, 42%.

Scheme 4^a

^aReagents and conditions: (a) 14, p-TSA, CHCl₃/acetone, 0 °C to rt, 4 days, 23%; (b) TMSOTf, CH₂Cl₂/MeNO₂, 0 °C to rt, 4 h, 57%; (c) NaOH, THF/H₂O, rt, 4 h, 63%; (d) NaHCO₃, 1-bromobutane, DMF, 165 °C, microwave irradiation, 12 min, 54%; (e) NaBH₄, MeOH, −78 °C, 2 h, 61%; (f) K-selectride, THF, −78 °C, 20 min, 52%; (g) NaBH₄, MeOH, rt, 1 h, 65%; (h) K-selectride, THF, rt, 3 h, 90%.