MORPHINE ANALOGS - RELATIONSHIP BETWEEN CHEMICAL-STRUCTURE AND INTERACTION WITH PROXIMAL TUBULAR TRANSPORTERS - CONTRALUMINAL ORGANIC CATION AND ANION TRANSPORTER, LUMINAL H+ ORGANIC CATION-EXCHANGER, AND LUMINAL CHOLINE TRANSPORTER/

In order to determine the role of different side groups in the interac tion with different transporters, luminal and contraluminal stop-flow microperfusion was applied, and the apparent Ki values (mmol/l) of twe lve morphine analogues were measured. Contraluminal organic cation tra nsporter (K-i,K-cl,K-NMeN+; N-l-methylnicotinamide): Those analogues w hich have an OH group on C atom 6 (normorphine, morphine, codeine, nor codeine) have higher K-i,K-cl,K-NMeN+ values (0.64-0.87 mmol/l) than t hose compounds which have an O group on C atom 6 (noroxymorphone, oxyc odone, hydrocodone, hydromorphone (0.14-0.24 mmol/l). Luminal H+/organ ic cation exchanger (K-i,K-l,K-MPP+; methylphenylpyridinium): analogue s with both a OCH3 group and a NCH3 group on C atoms 3 and 6, respecti vely, have higher K-i,K-l,K-MPP+ values than those where one or both C H3 groups were missing: codeine 5.1 --> norcodeine 0.5 or morphine 1.1 5; hydrocodone 1.0 --> hydromorphone 0.54; oxycodone 1.5 --> noroxymor phone 0.63. The K-i,K-cl,K-NMeN+ and K-i,K-l,K-MPP+ values of the 3 be ta- and 6 beta-glucuronide conjugates of morphine were much higher (> 10 mmol/l) than those of the other analogues. Luminal choline transpor ter (K-i,K-l,K-choline+): The tested analogues have K-i,K-l,K-choline values of between 6 and 25 mmol/l, except the glucuronide conjugates which do not inhibit at all. With the exception of the 14-OH compounds oxycodone and noroxymorphone, they show a similar inhibitory pattern as against the contraluminal NMeN+ transporter. Contraluminal organic anion transporter (K-i,K-cl,K-PAH; p-aminohippurate): 8 out of the 12 morphine analogues have K-i,K-cl,K-PAH values of between 5.7 and 7.3 m mol/l. Only the K-i values of codeine and the diacetyl and glucuronide conjugates are somewhat lower (2.1-3.5 mmol). The latter have K-i val ues against the cation transporters which are much higher than that of all other morphine analogues. The data indicate that the morphine ana logues are 'polysubstrates' that interact with different organic catio n transporters and the organic anion transporter. These transporters a re, therefore, rather unspecific. Furthermore, each transporter has hi s preference for certain side groups in the substrate molecules.