3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ8-THC and related compounds: synthesis of selective ligands for the CB2 receptor

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Abstract

The synthesis and pharmacology of 15 1-deoxy-Δ8-THC analogues, several of which have high affinity for the CB2 receptor, are described. The deoxy cannabinoids include 1-deoxy-11-hydroxy-Δ8-THC (5), 1-deoxy-Δ8-THC (6), 1-deoxy-3-butyl-Δ8-THC (7), 1-deoxy-3-hexyl-Δ8-THC (8) and a series of 3-(1′,1′-dimethylalkyl)-1-deoxy-Δ8-THC analogues (2, n=0–4, 6, 7, where n=the number of carbon atoms in the side chain−2). Three derivatives (1719

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Scheme 3. (a) (C6H5)3PCH3+ Br, n-BuLi/THF, 65°C; (b) LiAlH4/THF, 25°C; (c) KBH(sec-Bu)3/THF, −78 to 25°C then H2O2/NaOH.

) of deoxynabilone (16) were also prepared. The affinities of each compound for the CB1 and CB2 receptors were determined employing previously described procedures. Five of the 3-(1′,1′-dimethylalkyl)-1-deoxy-Δ8-THC analogues (2, n=1–5) have high affinity (Ki=<20 nM) for the CB2 receptor. Four of them (2, n=1–4) also have little affinity for the CB1 receptor (Ki=>295 nM). 3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ8-THC (2, n=2) has very high affinity for the CB2 receptor (Ki=3.4±1.0 nM) and little affinity for the CB1 receptor (Ki=677±132 nM).

Introduction

Traditional cannabinoid structure–activity relationships (SAR)1, 2, 3 state that a phenolic hydroxyl at C-1 of the cannabinoid skeleton is necessary for interaction with the CB1 receptor. However, we reported recently that 3-(1′,1′-dimethylheptyl)-1-deoxy-11-hydroxy-Δ8-tetrahydrocannabinol (1-deoxy-11-hydroxy-Δ8-THC-DMH, deoxy-HU-210, 1), a traditional cannabinoid lacking the 1-hydroxyl, has very high affinity for the CB1 receptor (Ki=1.2±0.1 nM), and exhibits characteristic cannabinoid in vivo pharmacology. Cannabinoid 1 also has exceptionally high affinity for the CB2 receptor (Ki=0.032±0.019 nM).4 A second 1-deoxy-cannabinoid, 3-(1′,1′-dimethylheptyl)-1-deoxy-Δ8-THC (1-deoxy-Δ8-THC-DMH, 2, n=5, where n=the number of carbon atoms in the side chain−2), is also potent in vivo, has significant affinity for the CB1 receptor (Ki=23±7 nM), and nearly 10 times higher affinity for the CB2 receptor (Ki=2.9±1.6 nM). 4 A group at Merck Frosst also described 1-deoxy-Δ8-THC-DMH; however, they found that it had an order of magnitude lower affinity for each receptor than we reported.5 This group also reported that two 1-methoxy cannabinoids, 1-methoxy-Δ8-THC-DMH (3) and 1-methoxy-Δ9(11)-THC-DMH (4), had affinities for the CB2 receptor in the 20 nM range, and virtually no affinity for the CB1 receptor.5 This is in contrast to traditional cannabinoids with a phenolic hydroxyl at C-1 which have similar affinities for both cannabinoid receptors.5, 6

The unexpected potency of 11-hydroxy-1-deoxy-Δ8-THC-DMH (1) was explained in terms of a possible interaction of the 11-hydroxyl with Lys 192 of the CB1 receptor.4 It is thought that this amino acid hydrogen bonds to the phenolic hydroxyl of traditional cannabinoids, and in a mutant receptor which lacks Lys 192, the affinities of the potent cannabinoids CP 55,940 and 11-hydroxy-Δ8-THC-DMH were greatly attenuated.7, 8 The potency of 1-deoxy-Δ8-THC-DMH (2, n=5) was rationalized on the basis of molecular modeling studies which suggested that this compound docked with the receptor in an orientation such that Lys 192 hydrogen bonds to the pyran oxygen.4 However, no rationalization was presented for the very high affinities of cannabinoids 1 and 2, n=5, for the CB2 receptor.4

In view of the selective affinity for the CB2 receptor reported for cannabinoids 1-5, 6-8, the synthesis of a number of additional 1-deoxy-cannabinoids has been carried out to obtain selective ligands for the CB2 receptor, and to explore the SAR of the 1-deoxy-cannabinoids at both cannabinoid receptors. Three series of compounds were synthesized which included simple 1-deoxy analogues of Δ8-THC, 1-deoxy-1′,1′-dimethylalkyl-Δ8-THCs, and 1-deoxynabilone analogues.

Section snippets

Results

Analogues of Δ8-THC included 11-hydroxy-1-deoxy-Δ8-THC (5), 1-deoxy-Δ8-THC (6), its 3-butyl (7), and 3-hexyl analogues (8). As outlined in Scheme 1, alcohol 5 was prepared from 2-bromo-5-pentylmethoxybenzene (9) and apoverbenone following the protocol employed in the synthesis of the dimethylheptyl analogue (1).4, 9, 10 The aryllithium derived from 9 was added to apoverbenone to give, after oxidative rearrangement, enone 10, dissolving metal reduction of which proceeded stereoselectively to

General

IR spectra were obtained using Nicolet 5DX or Magna spectrometers; 1H and 13C NMR spectra were recorded on a Bruker 300AC spectrometer. Mass spectral analyses were performed on a Hewlett–Packard 5890A gas chromatograph with a mass sensitive detector and HRMS data were obtained in the Mass Spectrometry Laboratory, School of Chemical Sciences, University of Illinois. Ether and THF were distilled from Na–benzophenone ketyl immediately before use, and other solvents were purified using standard

Acknowledgements

The work at Clemson was supported by grant DA03590, and that at Virginia Commonwealth University by grants DA03672 (B.R.M.) and DA05274 (M.E.A.), all from the National Institute on Drug Abuse.

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