| Citation | In 1972-73 Hughes was working in the Unit for Research on Addictive Drugs in Aberdeen. Already it had been shown that membrane fragments from brain had binding sites, with high and specific affinity for a number of narcotic analgesic drugs, both agonists and antagonists. The presence of endogenous opioids in tissues had long been forecast by Kosterlitz; Hughes began to look for evidence in late 1973. Knowing that opioids inhibit neurotransmitter release, Hughes showed that brain extracts could inhibit the contractual response of the isolated mouse deferens, stimulated through its nerve supply, an effect which was blocked by the antagonist naloxone. The eventual outcome which was achieved with others, was the isolation and characterisation of two pentapeptides, [Met]enkephalin and [Leu]enkephalin, both ligands of the delta-receptor. In 1983, Hughes became Director of the Parke-Davis Research Unit in Cambridge, where his work on opioids continues. He has developed interesting new ligands for, for example, the kappa-site, and compound CI-977 is highly selective for this site, raising the possibility of analgesia without some of the worst side effects of opiates, including abuse potential. More recently Hughes has been responsible for developing peptoids with high affinity for the CCK-B receptor. Antagonists with nanomolar binding constants and selective for CCK-B but not CCK-A receptors have been developed with pronounced anxiolytic activity. Curiously these antagonists potentiate the analgesic action of morphine and block development of tolerance. This latest work is important as it addresses unresolved problems in the opioid field. |