ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNew azacannabinoids highly active in the central nervous systemCheuk Man Lee, Harold E. Zaugg, Raymond J. Michaels, Anthony T. Dren, Nicholas P. Plotnikoff, and Patrick R. YoungCite this: J. Med. Chem. 1983, 26, 2, 278–280Publication Date (Print):February 1, 1983Publication History Published online1 May 2002Published inissue 1 February 1983https://pubs.acs.org/doi/10.1021/jm00356a031https://doi.org/10.1021/jm00356a031research-articleACS PublicationsRequest reuse permissionsArticle Views72Altmetric-Citations4LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Seven N-substituted 1,2,3,4-tetrahydro-1- and three 2-naphthylamines were prepared and tested for local anesthetic activity in the rabbit corneal reflex test and the mouse sciatic nerve block test. At 0.1 and 1%, three 1-alkylamino compounds had durations of action comparable to that of tetracaine in the rabbit corneal reflex test and were considerably more potent than lidocaine. The other four 1-alkylamino derivatives were inactive or at best minimally active. The durations of action of 1% concentrations of the three 2-alkylamino compounds were equivalent to that of 1% lidocaine in the corneal reflex test. In the mouse sciatic nerve block test, the three active 1-alkylamino compounds were considerably longer acting than either tetracaine or lidocaine. Three1-alkylamino and the three 2-alkylamino compounds showed toxicity equal to or greater than lidocaine, while two 1-alkylamino and two 2-alkylamino compounds showed toxicity equal to or greater than tetracaine by the intraperitoneal route in mice. N-Heptyl-1,2,3,4-tetrahydro-6-methoxy-1-naphthylamine methanesulfonate was the most promising local anesthetic in these series.

N-Heptyl-1,2,3,4-tetrahydro-6-met,hoxy-1-naphthylamine methanesulfonate (I) is a potent, long lasting local anesthetic. It was as potent as tetracaine and at least 10 times more potent than lidocaine in the rabbit corneal reflex, guinea pig wheal, and mouse sciatic nerve block tests. The threshold anesthetic concentration (TAC), defined as the concentration required to produce anesthesia lasting 5 min, was calculated from each linear regression line fitted to the log dose-duration data, and these values were used to compare the potencies of the local anesthetics. In the rabbit corneal reflex test, the TAC values were 0.04% for I. 0.04% for tetracaine, and 0.66% for lidocaine. In the guinea pig wheal test, I had a TAC of 0.02%, which was equipotent to tetracaine and 11 times more potent than lidocaine; epinephrine (1:100,000) prolonged the duration of action of all three local anesthetics but had the least effect with I. In the mouse sciatic nerve block test, the TAC values were 0.06% for I, 0.10% for tetracaine, and 0.86% for lidocaine. The acute LDm values of I in mice were 138 mg/kg sc and 26 mg/kg iv. By either route, I was less toxic than tetracaine and more toxic than lidocaine. Comparison of the LD50 and TAC values in the mouse sciatic nerve block test indicated that I had a greater therapeutic index than either reference standard.

AbstractAus den beiden bekannten Ausgangskomponenten (Ia) und (Ib) werden thermisch die Benzopyranopyridine (IIa) und (IIb) hergestellt, die zu O‐Derivaten (III) oder zu N‐Oxiden (IV) modifiziert werden.

Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the phenol retains biological activity and can lead to a greater selectivity of action, particularly the antinociceptive activity. The most interesting esters were 5, 6, 10, and 14 in the nitrogen analogs series and 19 and 20 in the carbocyclic series. Compound 5 was more potent than codeine in the writhing, hot-plate, and tail-flick tests and is at present undergoing clinical testing. Compound 20 was very potent in the mouse audiogenic seizure test and is of interest as an anticovulsant agent.

Various CNS-active cannabinoids in which the alicyclic ring was thiopheno, cyclopenteno, or cyclohexeno with the alkyl substituent in various positions (structural types 1-6) were synthesized by procedures described previously. These compounds were compared in selected pharmacological tests in mice, rats, dogs, and cats. The results suggested that methyl substitution in the close proximity of the phenolic hydroxyl group strongly influenced the activity of some cannabinoids, particularly of those which had a planar five-membered alicyclic ring rather than a six-membered ring.