George Mclean Milne

Selective and potent analgetics derived from cannabinoids.

Abstract: Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (—)‐9‐nor‐9β‐hydroxyhexahydrocannabinol (HHC). A new grouping, the 1‐methyl‐4‐phenylbutyloxy C‐3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C‐5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.

Enhancement of brain [3H]flunitrazepam binding and analgesic activity of synthetic cannabimimetics

Novel, synthetic cannabimimetics and delta 9-tetrahydrocannabinol were found to enhance the binding of [3H]flunitrazepam to mouse brain in vivo. This property, suggestive of facilitation of binding to benzodiazepine receptors, is consistent with the potentiation of the anticonvulsant activity of diazepam against pentylenetetrazol by these compounds. The relative potencies of delta 9-tetrahydrocannabinol and the new cannabimimetics for enhancing [3H]flunitrazepam binding in vivo could also be correlated with their relative analgesic efficacies. Similar pharmacological stereospecificity was displayed for both binding enhancement and analgesic effects. The following order of decreasing potency was observed: N-methyllevonantradol and (-)-CP-55,244 greater than levonantradol, canbisol, CP-42,096 and (-)-CP-55,940 greater than 9-beta-normethyl-9-beta-hydroxyhexahydrocannabinol, nabilone and CP-47,497 greater than delta 9-tetrahydrocannabinol. Dextronantradol, (+)-CP-55,940 and (+)-CP-55,244 were considerably less active than the respective (-)-enantiomers; cannabidiol was inactive. Extensive investigation of structure versus activity led to N-methyllevonantradol and the 3-(2-hydroxyphenyl)cyclohexanols derivative, (-)-CP-55,244, which are approximately 1000-fold more potent than delta 9-tetrahydrocannabinol.

The analgetic properties of piroxicam in animals and correlation with expreimentally determined plasma levels

In animal antinociceptive tests responsive to nonsteroidal anti-inflammatory drugs (NSAID), piroxicam is an extremely potent and effective analgetic at doses of 1–2 mg/kg p.o. In mice the plasma half-life and duration of analgetic action is short (t1/2=1.7 h), unlike man, wherein piroxicam exhibits an exceptionally long duration of action (half-life 40–45 h). An excellent correlation is observed between plasma levels and analgetic activity in the writhing test in mice suggesting that piroxicam will exhibit potent and long-lasting analgetic activity in man.

Levonantradol: A Role for Central Prostanoid Mechanisms?

Abstract: Although Δ9‐tetrahydrocannabinol (THC) possesses many pharmacologic activities, attempts to define sites of biochemical action for the natural cannabinoids have been hampered by their low solubility, their low potency, and their relative lack of biologic selectivity. We have recently described a potent, cannabinoid‐related analgetic, levonantradol, which acts stereospecifically in animals to produce analgesia qualitatively similar to morphine but at 1/9 to 1/34 the dose. While levonantradol does not act at or through the opiate receptor, the finding of one‐way cross tolerance in animals suggests that morphine and levonantradol influence common nociceptive pathways. This report describes a striking structural homology between PGE1 and levonantradol as elucidated by x‐ray and conformational studies. This observation is consistent with the generally recognized involvement of prostaglandins in pain and emesis and may have relevance to the site of levonantradols analgetic actions. More importantly, it provides an ongoing, heuristic basis for exploring, in depth, the role of prostaglandins in the action of levonantradol and cannabinoids.

Prototype cannabinoid analgetics, prostaglandins and opiates — A search for points of mechanistic interaction

Abstract While prototype cannabinoid analgetics such as levonantradol do not act at the opiate receptor, their opiate-like properties suggest a proximal site of action. Based on this reasoning we perceived a remarkable structural analogy between levonantradol and prostaglandin E2. We further postulated a three point receptor contact which enabled us to predict the minimum structural features for analgesia. In this report we describe a simple phenyl cyclohexanol ( 1 ) which was found to possess potent analgesia across a battery of analgetic assays and defines three key sites of receptor contact necessary for cannabinoid-like analgetic activity.

ONE WAY CROSS TOLERANCE FROM MORPHINE TO NANTRADOL - A POTENT, NON-OPIOID ANALGETIC

Summary Nantradol, a recently described cannabinoid-related analgetic, exhibits potent analgetic, antidiarrheal and antitussive effects in common with opioids. Unlike the opioids, however, nantradols analgetic action is not reversed by the antagonist naloxone. Furthermore, nantradol does not displace 3 H-dihydromorphine and is not discriminated as morphine in rats. However, animals made tolerant to morphine do exhibit one-way analgetic cross tolerance to nantradol. Plasma level determinations indicate that this cross tolerance can not be explained by morphine-induced alterations in pharmacokinetics. These findings, which extend earlier reports of morphine cross tolerance to δ 9 -tetrahydrocannabinol (THC), suggest that opioid and certain cannabinoid analgetics may share a common ultimate mechanism of analgetic action.

Cannabinoids: Definitional ambiguities and a proposal

Abstract Cannabinoids are usually defined ambiguously in either botanical, chemical or pharmacological frames of reference. For researchers attempting to dissect out useful agents with some, but not all of the pharmacological effects of marijuana, this is not a trivial, semantic issue, since designation of a compound as a cannabinoid carries with it an overlay of public perception and administrative policy concerns. A pharmacological definition is advocated, based primarily on the ability of compounds to be subjectively generalized from Δ 9 -THC. The alternate term cannabimimetic is advocated to signify such activity. Thus, compounds lacking the subjective effects of Δ 9 -THC, regardless of structural similarity, would not then be impeded by the often-deleterious cannabinoid label, while compounds sharing the subjective effect of Δ 9 -THC would be appropriately classified, despite structural divergence from the prototype.