Review of the Involvement of Opiate Receptors in Producing the Central and Peripheral Effects Caused by Two New Antidiarrheal Drugs,Loperamide and SC-27166

Abstract

A review of the morphinomimetic activities of the antidiarrheal drugs loperamide and nufenoxole (SC-27166) is presented. These agents bind, in an agonist manner, to opiate receptor sites of brain and myenteric plexus and probably produce their therapeutic actions and side effects through this receptor. Although both agents produce potent opiatelike effects in the myenteric plexus of the small intestine in vivo, CNS side effects are not seen until very high doses are administered. The narcotic-type abuse potential appears to be low for loperamide and may be even lower for nufenoxole. The marked separation of central and peripheral activities probably results from a differential pattern of absorption and distribution that results in a low concentration of drug at receptor sites in the brain and a high concentration at sites in the myenteric plexus.

References

Adelstein, G. W. , Yen, C. W. , Dajani, E. Z. , and Bianchi, R. G. (1976). 3,3-Diphenyl-3-(2-alkyl-1,3,4-oxadiazol-5-yl) propylcycloalkylamines, a novel series of antidiarrheal agents. J. Med. Chem. 19, 1221–1225.

Bianchi, C. , and Franceschini, J. (1954). Experimental observations on Haffner's method for testing analgesic drugs. Br. J. Pharmacol. 9, 280–284.

Clay, G. A. , Mackerer, C. R. , and Lin, T. K. (1977). Interaction of loperamide with 3H-naloxone binding sites in guinea pig brain and myenteric plexus. Mol. Pharmacol. 13, 533–540.

Colpaert, F. C. , Niemegeers, Cle. , and Janssen, P. A. J. (1976). The narcotic discriminative stimulus complex: Relation to analgesic activity. J. Pharm. Pharmacol. 28, 183–187.

Creese, I. , and Snyder, S. H. (1975). Receptor binding and pharmacological activity of opiates in the guinea pig intestine. J. Pharmacol. Exp. Ther. 195, 205–219.

Dajani, E. Z. , Bianchi, R. G. , East, P. E. , Bloss, J. L. , Adelstein, G. W. , and Yen, C. H. (1977). The pharmacology of SC-27166: A novel antidiarrheal agent. J. Pharmacol. Exp. Ther. 203, 512–526.

East, P. E., and Dudek, J. M. (1981). SC-27166, a new antidiarrheal: Evaluation for abuse liability using rat drug-discrimination and monkey drug self-administration procedures. Drug Development Res.

Eckenhoff, J. E. , and Oech, S. R. (1960). The effects of narcotics and antagonists upon respiration and circulation in man: A review. Clin. Pharmacol. Therap. 1, 483–524.

Eddy, N. B. , And Leimbach, D. (1953). Synthetic analgesics. II. Dithienylbutenyl A and dithienylbutylamines. J. Pharmacol. Exp. Ther. 107, 385–393.

10.

Fraser, H. F. , and Isbell, H. (1961). Human pharmacology and addictiveness of ethyl 1-(3-cyano-3,3-phenylpropyl)-4-phenyl-4 piperidine carboxylate hydrochloride (R-1132, diphenoxylate). Bull. Narcot. 13, 29–43.

11.

Heykants, J. , Michiels, M. , Knaeps, A. , and Brugmans, J. (1970). Loperamide (R. 18553), a novel type of antidiarrheal agent. Part 5: The pharmacokinetics of loperamide in rats and man. Arzneimittel-Forschung 24, 1649–1653.

12.

Jaffe, J. H. (1970). Narcotic analgesics. In: The Pharmacological Basis of Therapeutics. L. S. Goodman and A. Gilman (eds.). New York: The Macmillan Company, pp. 237–275.

13.

Janssen, P. (1976). Chapter 1. In: Synthetic Antidiarrheal Drugs: Synthesis-Preclinical and Clinical Pharmacology. W. Van Bever and H. Lal (eds.). New York: Marcel Dekker, Inc. pp. 1–5.

14.

Janssen, P. A. , Jageneau, A. H. , and Huygens, J. (1959). Synthetic antidiarrhoeal agents. I. Some pharmacological properties of R 1132 and related compounds. J. Med. Chem. 1, 299–308.

15.

Knoll, J. , Furst S. , and Makleit, S. (1977). The pharmacology of N substituted azido morphines. Arch. Int. Pharmacodyn. 228, 268–292.

16.

Kosterlitz, H. W. , and Watt, A. J. (1968). Kinetic parameters of narcotic agonists and antagonists, with particular reference to N-allylnoroxymorphone (Naloxone). Br. J. Pharmac. Chemother. 33, 266–276.

17.

Lal, H. , Gianutsos, G. , and Miksic, S. (1977). Discriminable stimuli produced by analgesics. In: Discriminative Stimulus Properties of Drugs. H. Lal (ed.). New York: Plenum Press pp. 23–45.

18.

Mackerer, C. R. , Brougham, L. R. , East, P. F. , Bloss, J. L. , Dajani, E. Z. , and Clay, G. A. (1977). Antidiarrheal and central nervous system activities of SC-27166 (2-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-3,3-diphenylpropyl)-2-azabicyclo (2.2.2) octane), a new antidiarrheal agent, resulting from binding to opiate receptor sites of brain and myenteric plexus. J. Pharmacol. Exp. Ther. 203, 527–538.

19.

Mackerer, C. R. , Clay, G. A. , and Dajani, E. Z. (1976). Loperamide, binding to opiate receptor sites of brain and myenteric plexus. J. Pharmacol. Exp. Ther. 199, 131–140.

20.

Niemegeers, C. , Lenaerts, F. , and Awouters, F. (1976). Preclinical animal studies of modern anti-diarrheals. In: Synthetic Antidiarrheal Drugs: Synthesis-Preclinical and Clinical Pharmacology. W. Van Bever , and H. Lal (eds.). New York: Marcel Dekker, Inc. pp. 65–114.

21.

Niemegeers, C. J. E. , Lenaerts, F. M. , and Janssen, P. A. J. (1974). Loperamide (R18553), a novel type of antidiarrheal agent. Part 2: In vivo parenteral pharmacology and acute toxicity in mice, comparison with morphine, codeine, and diphenoxylate. Arzneimittel-Forschung 24, 1636–1641.

22.

Pert, C. B. , Pasternak, G. , and Snyder, S. H. (1973). Opiate agonists and antagonists discriminated by-receptor binding in brain. Science (Washington) 182, 1359–1361.

23.

Sanvordeker, D. R. , and Dajani, E. Z. (1975). In vitro adsorption of diphenoxylate hydrochloride on activated charcoal and its relation to pharmacological effects of drug in vivo. J. Pharm. Sci. 64, 1877–1879.

24.

Scatchard, G. (1949). The attractions of proteins for small molecules and ions. Ann. N. Y. Acad. Sci. 51, 660–672.

25.

Schmidt, C. F. , and Livingston, A. E. (1933). The action of morphine on the mammalian circulation. J. Pharmacol. Exp. Ther. 47, 411–441.

26.

Stokbroekx, R. A. , Vandenberk, J. , Van Heertum, A. H. M. T. , Van Laar, G. M. L. W. , Van Der, A. A. , Vanbever, W. F. M. , and Janssen, P. A. J. (1973). Synthetic antidiarrheal agents. 2,2-Diphenyl-4-(4′-aryl-4′hydroxypiperidino)butyramides. J. Med. Chem. 16, 782–786.

27.

Thompson, J. W. (1958). Studies on the responses of the isolated nicititating membrane of the cat. J. Physiol. 141, 46–72.

28.

Wüster, M. , and Herz, A. (1978). Opiate agonist action of antidiarrheal agents in vitro and in vivo findings in support for selective action. N. S. Arch. Pharmacol. 301, 87–194.

29.

Wüster, M. , and Herz, A. (1976). Significance of physico-chemical properties of opiates for in vitro testing. In: Opiates and Endogeneous Opioid Peptides. Amsterdam: Elsevier/North-Holland Biomedical Press, pp. 447–454.