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ADDICTIVENESS OF TWO BENZIMIDAZOLE DERIVATIVES Preliminary Report

Hunger. et al (1) and Gross and Turian (2) have found that some basically substituted benzimidazole derivatives have analgesic activity. Since these compounds constitute a complately new chemical class of analgesics, two compounds were referred to the Addiction Research Center, USPHS Hospital, Lexington, Kentucky, for determination of their addictive potentialities in nan. This report presents the work accomplished prior to May 1, 1959. It is preliminary in nature and does not contain sufficient information to warrant any final statement of the addictiveness of the compounds as compared with norphine and codeine. It is presented at this time for purposes of information only.

The specific compounds referred for study were 1-(Beta-diethylaminoethy1)-2-(benzyl-4-chloro)-5-nitro benzimidazole (Ba-19390, NIH-7586, ARC 1-G-1) and 1-(Betadiethylaminoethyl)-2-(p-ethoxybenzyi)-5-nitrobenzinidazole methane sulfonate (Ba-20684, NIH-7607, ARC I-G-2). In this reoort, the drugs will be identified by their NIH code numbers.

As a class, these compounds possess a norphine-like spcctrum of pharmacological activity (2,3,4). They are

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analgesic in mice end rats, cause the Štraub reaction in mice, sedation and miosis in dogs, excitement and pupillary dilatation in cats, and respiratory depression in rabbits and other animals.

NIH-7586 was analgesic in mice (2,3,4) by both subcutaneous and oral routes [ED-50=l.5 mg/kg (3)]. In addicted monkeys, it was twice as potent as morphine in suppressing abstinence from morphine (5). Some preliminary clinical experimentation has been done in Switzerland (4). In man, NIH-7586 is reported to have a good analgesic effect in doses of 15 ag subcutaneousiy or 25-50 mg orally. Respiratory depression was reported after intravenous administration, no "excessive" respiratory depression after subcutaneous administration, and no respiratory depression after oral administration (4). However, Dr. N. B. Eddy received information that the compound was to be marketed for oral administratlon only because of respiratory depression after parenteral administration.

NIH-7607 is an extremely potent compound in animals. The ED-50 (subcutaneousiy) for analgesia in mice was 0.0012 mg/kg (3). NIH-7607 1s about 1700 times as potent as morphine in this speciss. NIH-7607 was 1500 times as potcnt (0.002 mg NIH-7607=3 mg morphine) subcutaneous1y in alleviating abstinence in the addicted monkey. No information on trials in man is available.

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Methods

Drugs. Because of reports of respiratory depression after parenteral administration, the orai route of administration was used exclusively. NIH-7586 was avallable in compressed tablets each containing 25 mg. NIH-7607 was given in solution in distilled water in concentrations of 0.01 and 0.l mg per ml. Drugs were administered with patients in the fasting state. Identity of the drugs was unknown to the patients but was known to the observers ("single-blind").

Effects of sinale doses. These tests were conducted in non-tolerant former morphine addicts who volunteered for the experiments. Drugs were adxinistered at 7:30 a.m. Observations were made at hourly intervals until Il:30 a.m. and at intervals of two hours thereafter until 9:30 p.m. At each observation the patient completed a simple questionnaire consisting of the following questions: "I feel the medicine": "The feelinglis like: morphine, marihuana, barbiturates, benzedrine, heroin"; "I dontt feel anything"; "I am relaxcd"; "1 have a drive"; "I am nauseated"; "I am sleepy"; and "I would like more". At each observation time, the diameter of the pupils was determined under conditions of constant light and accommodation by comparing the size of the pupils with those of blackened circles in 1-m steps on a card (Experienced observers agree as to

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size of pupil within l mm using this simple method). The aides also made general observations and notes on the behavior of the gatients. Initial doses used were 25 mg of NIl-7586 and 0.01 mg of NIH-7607. The doses were gradually increased from trial to trial until definite subjective and objective effects were obtained,after which a sufficient number of patients were given the dose found to be effective in the preliminary trials to permit a rough quantitative evaluation of potency in inducing subjective effects as compared with morphine or codeine,

In the case of NIh-7566, subjective and objective morphine-like effects began to appear when l00 mg were given, so 13 patients received this amount of the drug. In the case of NIh-?607, morphine-like effects began to appear whan two doses of 0.15 mg were administered at an interval of two and one-half hours, or after a single.dose of 0.25 mg.

The questionnaires completed by the patients were scored as negative (denial of any subjective effect), positive for opiates (effects reported to be like those of morphine or heroin), positive for other drugs (reported to be similar to those of barbiturates, marihuana,kor benzedrine), or questionable (some subjective effect reported but no definite identification of being simiiar to any drug was made).

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Difference in the size of the pupils after the drugs was calculated by subtracting the diameter after the drugs from the diameter prior to the drugs. The arca under the time action curve for pupillary constriction was then calculated by the method of Winter and Flataker (6).

Five patients wio were addicted tò and stabilized on é0 mg ng of morphine sulfate four times daily were available for these tests. The patients received their last dose of morphine at 4:00 p.m. In the succeeding twenty-four hours the patientsrreceived NIH-7586 and 7607 orally in doses end at intervals which were thought, on the basis of preliminary experiments, to be approximately equivalent to 10 to L0 per cent of the patients' accustomed dose of morphine, Since thase patisnts would have receivad three doses of 60 mg of morphine (total of 180 mg) in the 24-hour perlod (the fourth dose of 60 mg would fall at the 2hth hour), The doses of drugs under test were thought to be equivalent to 18 to 72 mg of morphine sulfate. In the case of NIh-7586, the doscs selected were 25 and 50 mg at 10:00 p.m., 6:00 a.m.and 10:00 a.m. of the test period. In the case of NIH-7607, the doses chosen were 0.05 and 0.1 mg at 10:00 p.m., 2:00 a.m., 6100 a.m., 10:00 a.m. and 12t00 M of the test period. Observations for the intensity of abstinence were hourly from the

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14th (6:00 a.m.) to the 24th (4:00 p.m.) hour after giving the last dose of morphine and the intensity of abstinence calculated in "hourly-polnts" by the method of Himmelsbach (7). The area under the time action curve was calculated by the system of Winter and. Flataker thus converting the data to a single figure, termed "point-hours".

The data were compared with data obtained in another experiment in which 9 patients recelved 18 mg (10 per cent of their accustomed dose), 36 mg (20 per cent), and 90 mg (50 per cent) of morphine sulfate subcutaneousiy in similar tests. Regression lines, estimate of the potency of NIH-7585 and NIH-7607 given orally as compared with the potency of morphine given subcutaneously, and 95 per cent confidence limits, were calculated according to the methods described by Bliss (8).

Results

Subjective Effects, The resuits are presented in Table 1 and are 'compared with the results obtained with 20 and 30 mg of morphine suifate orally and with 60 and 90 mg of codcine sulfate orally in another experiment. Five of 13 patients who received 100 mg of NIH-7586 reported that the effects were similar to those of an oplate, whereas 7 of 14 patlents who reccived 20 and 30 mg of morphine orally reported positively for opiates. In the case of codeine, 5 and 6 of l4 patients reported

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positively for opiates; thus, as judged by this system, NIH-7586 appears to be roughly one-third to one-fifth as potent as morphine in inducing subjective effects and is roughly equal to codeine in this respect. Six of 7 patients who received 0.25 mg of NIH-7607 reported positively for opiates. Therefore, NIH-7607 appears to be more than 80-l20 times as effective as morphine orally as an "euphcriant". Arter these doses of both NIH-7586 and 7607, behavior of the patients resembled that seen after morphine with alternating periods of somnolence and wakefulness ("coasting", "nodding"), scratching, increased loquaciousness, etc. being observed.

Puplllary Constriction. Mean figures for pupillary constriction expressed as the area under the tine action curves are shown in Table 2. The results, with respect to rough relative potencies of NIH-7586 and NIH-7607, agree with those described under "subjective effects".

Suppression.of Abstinence. Both. NIli-7566 and NIH-7607 partially suppressed abstinence from morphine in the doses used. The results ars shown in Figure 1. As indicated in the figure, I mg of morphine subcutaneously was equivalent to 2.62 (1.00-6.59) mg of N1H-7586 orally, and 1 mg of NIH-7607 orally was equivalent to 59.3 (15.55-136.5) mg of morphine subcutaneously. The curves

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met the requirements for significance of slope and parallelism. The figures in parentheses are the 95-per cent confidence limits.

Discussion

Both NIH-7586 and NIH-7607 induce morphine-1ike subjective effects and suppress symptons of abstinence from morphine. Both drugs, therefore, have addictive properties. The data, however, are insufficient to permit any statement about the degree of addictiveness as compared with morphine or codeine at this time. Further work on the relative euphcriant potencies, and cautious exploration of the effects of the two drugs when given hypodermically seems indicated. In addition, since these compcunds are the prototypes of a new chemical series of analgesics, a direct addiction experiment with one of them seems Indicated.

Quantitatively,NIH-7607 is the most potent suppressor of abstinence krown. It is, however, probably not as potent in man as in the monkey..

Sumuary

1. A preliminary examination of the addictive potgntiaiities of 1-(Beta-diethylaminoethyl)-2-(benzyl-4-chloro)-5-nitro benzimidazole (NIH-7586) and 1-(Betadiethylaminoethyl)-2-(p-ethoxybeney1)-5-nitrobenzimidazole methane sulfate (NIl-7607) has been made.

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2. Both NlH-7586 and NIH-7607 cause pupillary constriction and morphine-like subjective effects in nontolcrant former morphine addicts. NIH-7586 is 1/5th to 1/3rd as potent as morphine in inducing subjective effects, whereas NIl-7607 1s 80 to 120 times as potent as morphine.

3.Both NIli-7586 and NIH-7607 wi1l·suppress symptoms of abstinence from morphine.

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REFERENCES

2. GROSS, F. and TURRLAN, H.: Benzimidazole cerivatives vith marked analgesic action. Experientia 13: 4Gl-403 (0ct.) 1957..

5. DENEAU. G. A., McCARTHY, D. A., and SEEVERS, M. H.: physical dapendence liability studies in the monkey. Addendua 1, p. 11, Min. of 20th Meet. Committee on Drug Addiction and Narcotics, Natl. Acad. of Sci., Nati. Research Council, Div. Med. Sci. (Jan.) 1959.

6. WINTER, C. A. and FLATAiER, L.: Studies on Heptazone (6-Morpholino-4, 4-Diphenyl-3-Heptanone Hydrochloride) in Comparison with other Analgesic Agents. J. Pharmacol. and Exper. Therap. 981 305-317 (March) 1950.

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7. HIBELSBACH, C, K.: Studies of certain Addiction Characteristics of (a) Dihydromorphine ("Paramorphan"), (b) Dihycrodasoxymorphins-D ("Besomorphine"), (c) Dihydrodcsoxycodeinc-D ("Desocodeine"), aná (d) Methyldihydromorphinone ("ketopon"). J. Pharmacol. and Exper. Therap. 67: 239-249 (0ct.) 1939.

8. BLIsS, C. I.: The Statistics of Bioassay. New York. Academic Press Inc, 1952.

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Table 1

Subjective Effects of NIl-7586 (Ba-19390, 1-G-1) and N1H-7607 (Ba-20684, I-G-2) Given Ora11y

For method of- scoring, see text.

Figures in brackets represent patients who also reported positively for opiates.

\# Data from another experiment.

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Table 2

Pupillary Constriction After NIH-7586 (Ba-19390, 1-G-1) and N1H-7607 (Ba-20684, 1-G-2)

Data fron another experiment.

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