Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: Radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)[125I]iodocyanopindolol, [3H]mesulergine and [3H]Ketanserin

103

lit fiuoxetine, the N-demethylated metabolite ."" uoxetine exists in R-and S-enantiomeric fonns. S-Norfluoxetine inhibited serotonin (5-HT) uptake and I'Hlptlroxetine binding to 5-HT uptake sites with a pKi of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas l-norfluoxetine was 22 and 20 times, respectively, less pDltnt. R-and S-Norfluoxetine were less potent than the tlmSponding enantiomers of fluoxetine as inhibitors of WMpinephrine uptake and [3HJtomoxetine binding to WMpinephrine uptake sites. Ex vivo studies showed that S-norfluoxetine inhibited 5-HT uptake with an ED50 of 3 "8!kg intraperitoneally, 4.7 mglkg subcutaneously, and lEY WORDS: Fluoxetine; Norfluoxetine; Enantiomers; Strotonin 5-HT; Uptake; Inhibitors Ruoxetine, a selective inhibitor of serotonin (5-hydroxy lIyptamine, 5-HT) uptake (Wong et aI., 1974(Wong et aI., , 1975, has been successfully developed as an antidepressant drug (Feighner 1983;Beasley et al. 1990). Fluoxetine is de ftIoped and is marketed as the racemate, i.e., the R (-) and 5 (+) enantiomers of equal amounts. Both enantiomers inhibit 5-HT uptake and effectively pro duce functional responses associated with an increased S-HT transmission. There are no major differences in potency between R-and S-fluoxetine, and their eudis IIic ratio is close to unity (Wong et al., 1985(Wong et al., , 1990 9 mglkg orally (7.3, 11.4 and 21.9 Jimollkg, respectively), while the ED50 for R-norfluoxetine exceeded 20 mglkg intraperitoneally (48.6 Jimollkg). Inhibition of 5-HT uptake in cerebral cortex ex vivo and decrease in 5-HIAA levels in hypothalamus persisted for 24 hours after administration of S-norfluoxetine as demonstrated with the administration of fluoxetine. Thus, S-norfluoxetine is the active N-demethylated metabolite responsible for the persistently potent and selective inhibition of 5-HT uptake in vivo. Robertson et aI. 1988). Enzymatic N-demethylation is an early step of fluoxetine metabolism, and the de methylated compound norfluoxetine (Fig. 1) is a major metabolite (Parli and Hicks 1974; Lemberger et aI. 1978;Beasley et al. 1990) in laboratory animals and in man. Norfluoxetine is also a potent and selective inhibitor of 5-HT uptake (Wong et aI. 1975; Horng and Wong 1976;Fuller et al. 1978). In the present communication, we report the pharmacologic pro&les of R-and S-norfluox etine, which have been recently synthesized in high enantiomeric purity. In contrast with the two enan tiomers of fluoxetine, however, we have found that S-norfluoxetine is over 20-fold more potent than the R enantiomer as an inhibitor of 5-HT uptake both in vitro and in vivo. MATERIALS AND METHODSMale Sprague-Dawley rats weighing between 100 and 150 g (Harlan Industries, Cumberland, IN) were housed in a room with a 12-hour dark/light cycle at 23°C, and

Section: Methodsmentioning

confidence: 99%

Norfluoxetine Enantiomers as Inhibitors of Serotonin Uptake in Rat Brain

Wong

Bymaster

Reid

et al. 1993

103

“…Serotonin recep tors are classifIed as 5-HTI and 5-HT2 (Peroutka and Snyder 1979) and at least three subtypes, 5-HTIA, 5-HT18, and 5-HTlC have been characterized in rats (Pedigo et al 1981;Hoyer et al 1985;Peroutka 1986). When tested under conditions in which MDMA in creases locomotion, direct agonists at both 5-HTIA and 5-HTlC/2 receptors consistently decrease locomotor ac tivity.…”

mentioning

confidence: 99%

Serotonin1B Receptor Activation Mimics Behavioral Effects of Presynaptic Serotonin Release

Rempel

Callaway

Geyer

1993

“…Earlier studies using nonselective 5-HT antagonists had predicted up regulation of 5-HTI receptors, but so far, no 5-HTI sub type has exhibited upregulation after chronic 5-HT antagonist treatment at a 10 mg/kg dose (Pranzatelli 1991;Pranzatelli et al 1993). Offord et al 1988;Hoyer et al 1985). The affinity of metergoline and methiothepin should be sufficient to demonstrate trophic effects with chronic administra tion at the dose used.…”

Section: Discussionmentioning

confidence: 99%

“…antagonists (Glennon 1987;Middlemiss 1985), drugs for which behavioral data are available. However, TFMPP and m-CPP have activity at 5-HT l C sites and RU 24969, TFMPP, m-CPP and quipazine also bind to 5-HT 2 sites (Hoyer et al 1985). [ l 25I]ICYP has been used to selectively labe15-HTlB sites in the presence of isoproterenol to suppress binding to j3-adrenoceptors (Offord et al 1988;Ariani et al 1989;Pleus and Bylund 1992).…”

mentioning

confidence: 99%

Drug-Induced Regulation of [125I]Iodocyanopindolol-labeled 5-Hydroxytryptamine1B Receptor Binding Sites in the Central Nervous System

Pranzatelli

Razi

1994

Little is known about the regulation of 5-hydroxytryptaminelB (5-HT1B) receptors, a putative terminal autoreceptor in the central nervous system. We studied the regional responses of [ 1 25IJiodocyanopindolol ([ 1 25!]ICYP)-labeled central 5-HT1B sites to chronic treatment with 5-HT agonists and antagonists at a dose of 10 mglkgld IP for 30 consecutive days in the rat. In controls, there were 3.4-fold regional differences in Bmax , with a rank order of brainstem > hippocampus> cortex, striatum> spinal cord, and Kas were slightly lower in striatum and spinal cord. RU 24969 significantly reduced Bmax 23 to 63% in cortex, hippocampus, striatum, brainstem, and spinal cord without a change in Ka except for a 1.7-fold increase in cortex and spinal cord. The