jwh-018 and 3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

The human cannabinoid subtype 1 receptor (hCB

Topics: Animals; beta-Arrestin 2; Cannabinoid Receptor Agonists; CHO Cells; Cricetulus; Cyclohexanols; GTP-Binding Proteins; Indoles; Male; Mice; Naphthalenes; Quinuclidines; Receptor, Cannabinoid, CB1

Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01 mg/kg) and decreased response rate (ED50=0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ9-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ9-THC decreased rectal temperature by 2.2 and 2.8°C, respectively; the doses decreasing temperature by 2°C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.

Topics: Animals; Benzoxazines; Body Temperature; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Conditioning, Operant; Cyclohexanols; Discrimination Learning; Dronabinol; Hypothermia; Indoles; Macaca mulatta; Male; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Synthetic cannabinoids (CBs) [naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073)] are marketed, sold, and used as alternatives to cannabis. Synthetic CBs appear to have effects similar to those of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the drug primarily responsible for the behavioral effects of cannabis. However, synthetic CB products produce atypical effects (e.g., hypertension, seizures, and panic attacks). One potential explanation for atypical effects is CB₁ receptor agonist efficacy, which is reportedly higher for JWH-018 and JWH-073 compared with Δ⁹-THC. The goal of this study was to test a prediction from receptor theory that tolerance/cross-tolerance (i.e., resulting from daily Δ⁹-THC treatment) is greater for a low-efficacy agonist compared with a high-efficacy agonist. Rhesus monkeys discriminated 0.1 mg/kg Δ⁹-THC i.v. from vehicle, and sensitivity to CB(1) agonists was determined before and after 3 and 14 days of Δ⁹-THC treatment (1 mg/kg per day s.c.). (1R,3R,4R)-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP-55,940), a prototype high-efficacy CB₁ receptor agonist, JWH-018, and JWH-073 substituted for the discriminative stimulus effects of Δ⁹-THC. Three days of Δ⁹-THC treatment produced less tolerance/cross-tolerance than 14 days of Δ⁹-THC treatment. Three days of Δ⁹-THC did not result in cross-tolerance to CP-55,940, JWH-073, and JWH-018; in contrast, as reported previously, 3 days of Δ⁹-THC treatment decreased sensitivity to Δ⁹-THC 3-fold. Fourteen days of Δ⁹-THC decreased sensitivity to Δ⁹-THC, CP-55,940, JWH-018, and JWH-073 9.2-fold, 3.6-fold, 4.3-fold, and 5.6-fold, respectively. The greater loss of sensitivity to Δ⁹-THC relative to CP-55,940 and JWH-018 suggests that differences in CB₁ receptor agonist efficacy are important in vivo and might underlie differences in the dependence liability and adverse effects of synthetic CBs versus cannabis.

Topics: Animals; Cannabinoids; Cannabis; Cyclohexanols; Dronabinol; Drug Tolerance; Female; Indoles; Macaca mulatta; Male; Naphthalenes; Receptor, Cannabinoid, CB1

A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9-11) and 2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (12-14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB(1) receptor by hydrogen bonding to the carbonyl group. Indoles 9-11 have significant (K(i)=17-23nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles (5, 15, 16). 2-Methyl-1-indoles 12-14 have little affinity for the CB(1) receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17-19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon (26) was synthesized and found to have K(i)=26+/-4nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener (19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB(1) receptor.

Topics: Cannabinoids; Cyclohexanols; Dronabinol; Hydrogen Bonding; Indicators and Reagents; Indoles; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Naphthalenes; Receptors, Cannabinoid; Receptors, Drug; Spectrophotometry, Infrared; Stereoisomerism; Structure-Activity Relationship