Anti-nociceptive effects in N-substituted cyclohexylmethylbenzamides
This is a brief article on the totally synthetic, totally unrelated to any controlled compound, opioid
analgesic AH-7921. Both the 3,4 dichloro & the N,N dimethyl are needed to produce a potent analgesic...
British journal of pharmacology 49 (1): 158P–159P
R. T. BRITrAIN, D. N. KELLETT, M. L. NEAT & R. STABLES
Department of Pharmacology, Allen & Hanburys Limited, Ware and Huntingdon Research Centre, Huntingdon.
In the mouse, certain N-substituted cyclohexylmethylbenzamides markedly inhibited writhing induced by phenylquinone and the nociceptive responses to being placed on a hot plate (Table 1). The results indicated that these compounds possessed analgesic activity and [3,4-dichloro-N-fl-(dimethylamino)cyclohexyl] methylbenzamide (AH 7921) was selected for detailed study in higher species.
In the conscious dog the minimal oral effective doses of AH 7921, morphine
required to completely suppress the pain response to electrical stimulation of the dental pulp (Neat & Peacock, 1971) were 1.25±0.8, 1.25±0-3 and 3.5±0±6 mg/kg respectively. In a similar test using the conscious rhesus monkey the minimal antinociceptive doses of AH 7921, morphine and codeine were 13.8±1-2, <5.0 and 11.3±0.8 mg/kg espectively. Anti-nociceptive doses of AH 7921 caused no overt behavioural effects in the mouse, dog or monkey but higher doses (50 mg/kg orally) caused slight central nervous system depression. The addictive liability of AH 7921 was next investigated. AH 7921 was administered orally to rats, 5 mg/kg 3 times a day increasing to 20 mg/kg 3 times a day over 5 days. On the fifth day the animals were challenged with naloxone 0.25 mg/kg s.c., which caused an abstinence syndrome similar to that produced in animals that had received morphine on a similar dosage schedule. In the rhesus monkey single doses of AH 7921, 5-10 mg/kg s.c., completely alleviated the abstinence syndrome in morphine-dependent animals. In addition, AH 7921, 7-5 mg/kg s.c. twice daily, increasing to 30 mg/kg s.c. twice daily over 30 days, produced physical dependence
in naive monkeys which was demonstrated in two ways. Nalorphine, 2 mg/kg s.c., induced an abstinence syndrome typical of that seen following morphine withdrawal in morphine-dependent monkeys. Secondly, on terminating AH 7921 treatment abstinence signs appeared over a period of 24-48 h. AH 7921 would be classed as a narcotic analgesic having high addictive liability. These findings are relevant to the relationship between structures of morphine-like compounds and addictive liability.
TABLE 1. Anti-nociceptive effects of some N-substituted cyclohexylmethylbenzamides in the mouse
Phenylquinone test Hot plate test
AH no. R, R2 ED50 mg/kg orally ED50 mg/kg s.c.
7563 -N(CH,)2 15-3 (7-6-31-0) 15-5 (5-4-42-0)
8533 2Cl -N(CH,)2 >100 60
8532 3Cl -N(CHS)2 16-0(8-4-34-0) 95 (4-3-24-5)
8529 4Cl -N(CH,)2 7-3(3-3-16-1) 50(1-7-15)
7921 3,4Cl -N(CHS)2 0-85 (0-4-1*7) 2-5 (1-2-6-4)
7959 3,4Cl piperidine >100 > 100
8507 3,4Cl N-methyl piperizine >100 >100
Morphine 11 (0-7-1-8) 2-8(1-1-48)
Codeine 5 8 (2-9-11-6) 17-0(9-1-32-0)
We would like to thank Dr. G. B. A. Veitch, University of Aston, Birmingham and the Research Chemists of the External Projects Unit, Allen & Hanburys Ltd., Ware for the synthesis of the compounds used in this work.
NEAT, M. L. & PEACOCK, R. (1971). Implantation of electrodes in the dentine of an upper canine tooth in the dog. Br. J. Pharmac., 43, 476-477P.