European Journal of Pharmacology, 70 (1981) 445--451 445 © Elsevier/North-Holland Biomedical Press THE IRREVERSIBLE NARCOTIC ANTAGONISTIC AND REVERSIBLE AGONISTIC PROPERTIES OF THE FUMARAMATE METHYL ESTER DERIVATIVE OF NALTREXONE * A.E. TAKEMORI **, DENNIS L. LARSON and P.S. PORTOGHESE Department of Pharmacology, Medical School (A.E.T.), and Department of Medicinal Chemistry, College of Pharmacy (P.S.P., D.L.L.), University of Minnesota, Minneapolis, Minnesota 55455, U.S.A. Received 26 September 1980, revised MS received 9 December 1980, accepted 16 December 1980 A.E. TAKEMORI, D.L. LARSON and P.S. PORTOGHESE, The irreversible narcotic antagonistic and reversible agonistic properties of the fumaramate methyl ester derivative of naltrexone, European J. Pharmacol. 70 (1981) 445--451. The fumaramate methyl ester derivatives of naltrexone (~-FNA) and oxymorphone (~-FOA) were both found to be reversible agonists on the guinea pig ileal longitudinal muscle preparation. In addition, ~-FNA possessed an irreversible antagonistic effect against morphine whereas /3-FOA had no such capacity. Analysis by PA2 values revealed that ~-FOA resembled pure agonists like morphine and enkephalin while ~-FNA resembled the mixed agonist-antagonists like nalorphine and pentazocine. The antagonism by ~-FNA was very selective in that it antag- onized pure agonists but had little or no effect on the effects of either mixed agonist-antagonists, ethylketo- cyclazocine or other non-opiate-type agonists like norepinephrine. Fumaramate methyl ester derivative Naltrexone Guinea pig ileum Opioid receptor Oxymorphone Agonist Antagonist Narcotic 1. Introduction The concept of multiple opioid receptors and multiple modes of interaction with a single receptor was first proposed by Portho- ghese in 1965 (Portoghese, 1965; 1966). Since then certain pharmacological studies have supported this concept {Martin, 1967; Takemori et al., 1969; Smits and Takemori, 1970). More recently, the multiple receptor concept has been advanced through a number of in vitro and in vivo biological assays and the opioid binding assay and these have been summarized in several reviews (Lord et al., * This work was supported by U.S. Public Health Ser- vice Grants DA00289 and DA01533 from the Na- tional Institute on Drug Abuse. ** To whom correspondence should be addressed: Department of Pharmacology, University of Minne- sota, 435 Delaware Street S.E., 3-260 Millard Hall, Minneapolis, Minnesota 55455, U.S.A. 1977; Martin, 1978; HSllt and Wfister, 1978; Snyder and Childers, 1979; Smith and Loh, 1980). We have recently reported in a preliminary communication, the synthesis of the fi-fumar- amate methyl ester derivative of naltrexone (~-FNA) (Portoghese et al., 1980). This deriv- ative appears to have greater selectivity in covalent bond formation than our earlier nitrogen mustard receptor probes, chlornal- trexamine (fi-CNA) and chloroxymorphamine (~-COA)(Portoghese et al., 1978; 1979; Caruso et al., 1979; 1980). We now report the detailed studies of the agonistic and antag- onistic effects of ~-FNA on the guinea pig ileal longitudinal muscle preparation and addi- tional support for the concept of multiple opioid receptors or multiple modes of interac- tions with a single population of opioid recep- tors.