19,19-Dimethylheptyl-D-8-tetrahydrocannabinol-11-oic Acid: A Novel, Orally Effective Cannabinoid with Analgesic and Anti-inflammatory Properties

19,19-Dimethylheptyl-D-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid that is under development by Atlantic Pharmaceuticals as an anti-inflammatory and analgesic drug. The objective of the study was to investigate the effects of CT-3 on overt symptom complex (Irwin’s test), nociception, gastrointestinal (GI) ulceration, and pharmacological availability after intragastric (i.g.) and intraperitoneal (i.p.) administration. Analgesic studies were assessed in the hot-plate (55°C) and the tail clip tests in mice and in the tail clip test in rats. In addition, pharmacological interaction of CT-3 with the solvent dimethyl sulfoxide (DMSO) was investigated in rats. In mice, CT-3 decreased spontaneous motor activity and induced dose-dependent, analgesic activity in the tail clip and hot-plate tests, with potency similar to morphine sulfate after i.g. and i.p. administration. However CT-3 showed more prolonged duration of analgesic action than morphine. In rats, CT-3 showed marked analgesia in the tail clip test and had similar i.p. and i.g. median effective dose (ED50 values; 5 mg/kg). CT-3 was devoid of GI ulceration when administered with DMSO either acutely at doses below 100 mg/kg or chronically at a dosage of 30 mg/ kg/day for 5 days. In contrast, indomethacin induced GI ulceration and deaths. The concurrent use of DMSO with CT-3 decreased its analgesic action, increased its adverse central nervous system effects, and induced GI ulceration. The evidence indicates that CT-3 exhibits a large dissociation between its anti-inflammatory/analgesic effects and its ulcerogenic actions. CT-3 warrants clinical development as a novel anti-inflammatory and analgesic drug. 19,19-Dimethylheptyl-D-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid with analgesic and anti-inflammatory activities (Burstein et al., 1992). CT-3 is chemically similar to D-9-tetrahydrocannabinol (THC, dronabilone) and nabilone (Eli Lilly, Indianapolis, IN), differing only in the substitutions made on C3 and C9 positions (Fig. 1). The analgesic activity of CT-3 was demonstrated in the mouse hot-plate (48°C) and phenylquinone writhing tests when administered in various oil-based vehicles (Burstein et al., 1998) or with the solvent dimethyl sulfoxide (DMSO) (unpublished study; Atlantic Pharmaceuticals, Raleigh, NC). The anti-inflammatory effects of CT-3 were well established in the mouse air pouch and the rat adjuvant arthritis tests with an approximate intragastric (i.g.) ED50 value of 0.1 mg/kg (Zurier et al., 1998). The possibility that unpredictable bioavailability could have occurred when CT-3 was administered in nonoptimum vehicles precluded defining desirable pharmacological actions (e.g., analgesic and anti-inflammatory activities) from undesirable actions (e.g., ulcerogenic and central nervous system activities), if any. In addition, little is known about high-dose pharmacology, toxicity, pharmacological availability of CT-3 after oral and parenteral administration, or possible interaction with DMSO. To address these issues, the objectives of the present study were: 1) to investigate the analgesic action of CT-3 in the mouse hot-plate and tail clip tests in comparison with the reference standard, morphine sulfate; 2) to investigate the acute effects of CT-3 on symptom complex, analgesia, gastrointestinal (GI) ulcerogenicity, and toxicity in rats when administered in an aqueous suspension that contained DMSO; 3) to investigate the effects of CT-3 administered without DMSO, either orally or intraperitoneally (i.p.), on symptom complex, analgesia, GI ulcerogenicity, and toxicity in rats; and 4) to investigate the chronic (5 days) Received for publication August 12, 1998. 1 This research was funded by Atlantic Pharmaceuticals, Inc. (Raleigh, NC). The authors also acknowledge additional support received from the International Drug Development Consultants Corporation and the Department of Research of the Salt Lake Veterans Administration Medical Center. ABBREVIATIONS: CT-3, 19,19-dimethylheptyl-D-8-tetrahydrocannabinol-11-oic acid; i.g., intragastric; i.p., intraperitoneal; THC, D-9-tetrahydrocannabinol; DMSO, dimethyl sulfoxide; MC, methylcellulose; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug. 0022-3565/99/2911-0031$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 291, No. 1 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 291:31–38, 1999 31 at A PE T Jornals on Jauary 8, 2018 jpet.asjournals.org D ow nladed from