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Binding and structure‐activity‐relation of benzo[f]isoquinoline‐ and norcodeinone‐derivatives at μ‐opioid receptors in the rat cerebral cortex

1 We have probed the ligand binding site of the μ‐opioid receptor using a series of isoquinoline‐ and norcodeinone‐derivatives; in these morphine‐ and codeine‐analogues, the position of the piperidine‐nitrogen as well as its mobility is altered relative to that found in morphine. 2 The μ‐receptor in rat cortical membranes was labelled with [3H]‐naloxone and competition experiments were carried out in the absence and presence of Gpp(NH)p and NaCl: conditions, which are associated with affinity shifts for agonists whilst antagonist affinity remains unaffected. Moving the piperidine‐nitrogen closer to the phenolic ring or reducing its mobility by incorporation into an additional ring drastically decreases the affinity. 3 In contrast, we find that the piperidine‐nitrogen in a distal position is well tolerated provided that additional structural criteria, in particular a phenolic hydroxyl‐group and a 6 carbon ring corresponding to ring C in morphine, are met. This assumption was verified by the synthesis of WB4/PH (4aR, 10bS, 11R)‐10, 11‐epoxy‐1, 2, 3, 4, 5, 6‐hexahydro‐9‐hydroxy‐3‐methyl‐4a,10b‐butano‐benzo[f]isochinolin‐12‐on(10). This compound is an agonist with an affinity comparable to that of morphine. 4 We therefore conclude that both the mobility of the piperidine nitrogen of the ligand and of its counterpart anionic site in the ligand binding pocket of the μ‐opioid receptor (presumably aspartic acid) are important determinants for fruitful interaction. The mobility of the anionic site is restricted in one direction but is sufficient to bridge the 2Å distance that exists between the position of the nitrogen in morphine and WB4/PH.