Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms

Mild Generation of o-Quinone Methides. Synthesis of (-)-Hexahydrocannabinol and Dihydrocannabidiol

(-)-Hexahydrocannabinol 7 was synthesized enantioselectively under mild conditions through the ortho quinone methide mediated cyclization of the adduct of R-(+)-citronellal and the bisethoxyethyl ether of olivetol. The conditions enabled the ene product, 1, 2-dihydrocannabidiol6, to be isolated as well

Synthesis of Rotationally Restricted Tetrahydrocannabinol Ethers

Two rotationally restricted tetrahydrocannabinol (THC) ethers were synthesized to test the concept that the psychopharmacological activity of cannabinoids derives, in part, from the orientation of the lone pairs of electrons of the phenolic hydroxyl oxygen. These compounds, 0,2-propano-A6-THC (3) and 0,lO-methano-Ag-THC (12), lock the orientation of the lone pairs of electrons toward and away from the cyclohexene ring, respectively, by restricting bond rotation through the formation of cyclic ethers. The synthesis of 3 was achieved by alkylation of the phenolic oxygen of A8-THC (1) with 3-bromo-1-propanol followed by cyclodehydration in the presence of phosphorus pentoxide. The synthesis of 12 was achieved from a sequence of reactions that involved the cyclization of a chloroformate in a modification of the Darzens acylation of olefins. Thus, treatment of AS-THC with phosgene in the presence of NJV-dimethylaniline afforded A9-THC chloroformate. Subsequent intramolecular cycloaddition of the chloroformyl moiety to the Ag-unsaturation in the presence of AlC1, afforded the corresponding 0-chloro ester 9. Treatment of 9 with lithium aluminum hydride gave 10-(hydroxymethy1)-AS-THC (10). Compound 12 and 10-methylene-A8-THC (11) were obtained as a readily separable mixture by treatment of 10 with 3 mol of tosyl chloride in pyridine. I3C NMR and IH NMR spectral assignments were made. A model study of the TiC14-mediated cleavage of the MEM ether of phenol demonstrated generation of the phenoxymethyl cation

Investigation of the Role of the Phenolic Hydroxyl in Cannabinoid Activity

Structure-activity relationship studies have suggested that the phenolic hydroxyl group is essential for the pharmacol. activity of the cannabinoids. However, it remains to be established whether it is the hydrogen of the phenolic hydroxyl that is important (possibly because this hydrogen can participate in a hydrogen bonding interaction) or whether it is the oxygen of the phenolic hydroxyl that is important (possibly because one of the lone pairs of electrons on this oxygen can serve as a hydrogen bond acceptor). Two new etherified cannabinoids were prepd. in which the phenolic hydroxyl oxygen is incorporated into a fourth ring. These new compds. were designed to test the importance both of the phenolic hydroxyl oxygen and of the orientation of its lone pairs of electrons for cannabinoid pharmacol. activity. O,2-Propano-Δ8-tetrahydrocannabinol (0,2-Propano-Δ8-THC) was designed to mimic Δ9-THC in its phenol conformation I (C2-C1-O-H-7°). O,10-Methano-Δ9-tetrahydrocannabinol (0,10-Methano-Δ9-THC) was designed to mimic Δ9-THC in its phenol conformation II (C2-C1-O-H = 167°). Mol. mechanics calcns. revealed that 1) there are two accessible min. energy conformers for O,2-propano-Δ8-THC, which differ principally in the conformation of the new fourth ring, and 2) there are three accessible min. energy conformers for O,10-methano-Δ9-THC, the first two of which differ mainly in the conformation of the new fourth ring, whereas the third possesses an alternate pyran ring conformation. Wave function and mol. electrostatic potential (MEP) maps were calcd. for each accessible conformer of O,2-propano-Δ8-THC and of O,10-methano-Δ9-THC. The resultant MEP maps compared well with the corresponding MEP maps generated for Δ9-THC in each of its two min. energy conformations (two phenolic hydroxyl positions). These results imply that 1) O,2-propano-Δ8-THC should be capable of being recognized at a site that would recognize Δ9-THC in its phenol conformation I and 2) O,10-methano-Δ9-THC should be capable of being recognized at a site that would recognize Δ9-THC in its phenol conformation II. Pharmacol. evaluation of the analogs revealed that O,10-methano-Δ9-THC was inactive in all mouse tests, as well as the rat drug discrimination model. O,2-Propano-Δ8-THC was similar to Δ8-THC in that it depressed rectal temp. and produced antinociception and ring immobility in mice. However, it differed from Δ8-THC in that it only weakly depressed locomotor activity and failed to substitute for Δ9-THC in the drug discrimination paradigm. A similar sepn. of cannabinoid pharmacol. effects has not been possible heretofore. These results suggest that the orientation of the lone pairs of electrons on the phenolic hydroxyl oxygen plays an important role in the mediation of some, but not all, behavioral effects of the cannabinoids

A Rational Search for the Separation of Psychoactivity and Analgesia in Cannabinoids

The compd. 9- beta-hydroxy-hexahydrocannabinol [(-)-9β-OH-HHC] was designed to fit a combined theor. profile of an analgesic cannabinoid (equatorial alc. at C-9, phenol at C-1 and a C-3 side chain) with reduced psychoactivity (axial C-9 substituent which protrudes into the α face). (-)-9β-OH-HHC was synthesized by the addn. of Me Grignard to 9-oxo-11-nor-HHC. Its α epimer was obtained by the regiospecific epoxide ring opening of 9α, 10α-epoxy-HHC acetate. (-)-9β-OH-HHC and (-)-9α-OH-HHC were each evaluated in a battery of tests in mice and were found to be 10-25 times less potent than (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) in all tests including the tail flick test for antinociception (analgesia). Mol. mechanics calcns. [MMP2(85)] revealed that, in the global min. energy conformation of (-)-9β-OH-HHC, the axial Me at C-9 protrudes into the α face of the mol., while the axial hydroxyl at C-9 in (-)-9α-OH-HHC protrudes into this same face. These calcns. also identified a higher energy carbocyclic ring (twist) conformer of each in which there is no protrusion of a C-9 substituent of the carbocyclic ring into the α face. The minimal activity of both compds. is attributed to these higher energy forms. It is concluded that protrusion of a C-9 substituent into the α-face of the mol. is assocd. with reduced cannabinoid analgesia, as well as with reduced cannabinoid psychopharmacol. activity

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms

The Design, Synthesis and Testing of Desoxy-CBD: Further Evidence for a Region of Steric Interference at the Cannabinoid Receptor

Cannabidiol CBD, a non-psychoactive constituent of marihuana, has been reported to possess essentially no affinity for cannabinoid CB1 receptor binding sites in the brain. Our hypothesis concerning CBD\u27s lack of affinity for the cannabinoid CB1 receptor is that CBD is not capable of clearing a region of steric interference at the CB1 receptor and thereby not able to bind to this receptor. We have previously characterized this region of steric interference at the CB1 receptor [P.H. Reggio, A.M. Panu, S. Miles J. Med. Chem. 36, 1761–1771 (1993)] in three dimensions using the Active Analog Approach. We report here a conformational analysis of CBD which, in turn, led to the design of a new analog, desoxy-CBD. Modeling results for desoxy-CBD predict that this compound is capable of clearing the region of steric interference by expending 3.64 kcal/mol of energy in contrast to the 12.39 kcal/mol expenditure required by CBD. Desoxy-CBD was synthesized by condensation of 3-pentylphenol with p-mentha-2,8-dien-l-ol mediated by DMF-dineopental acetal. Desoxy-CBD was found to behave as a partial agonist in the mouse vas deferens assay, an assay which is reported to detect the presence of cannabinoid receptors. The compound produced a concentration related inhibition of electrically-evoked contractions of the mouse vas deferens, possessing an 50 of 30.9 nM in this assay. Taken together, these results support the hypothesis of the existence of a region of steric interference at the CB1 receptor. While the energy expenditure to clear this region was too high for the parent compound, CBD, the removal of the C6\u27 hydroxyl of CBD produced a molecule (desoxy-CBD) able to clear this region and produce activity, albeit at a reduced level