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Biotech / Medical : TITAN PHARMACEUTICAL (TTP) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (44)	4/20/1999 11:09:00 AM
From: scaram(o)uche	Read Replies (1) \| Respond to of 362

just a little background regarding the abstract by Morriset et al.... Naunyn Schmiedebergs Arch Pharmacol 1996 Feb;353(3):290-4 The moderate affinity of clozapine at H3 receptors is not shared by its two major metabolites and by structurally related and unrelated atypical neuroleptics. Schlicker E, Marr I Institut fur Pharmakologie und Toxikologie, Rheinische Friedrich-Wilhelms-Universitat Bonn, Germany. We determined the affinity and/or potency of two metabolites of clozapine (clozapine-N-oxide and N-desmethylclozapine) and of five atypical neuroleptics, chemically related (olanzapine) or unrelated to clozapine (remoxipride, risperidone, thioridazine, zotepine), at H3 receptors. The specific binding of 3H-N alpha-methylhistamine to rat brain cortex homogenates was inhibited by the seven compounds; the pKi values were: N-desmethylclozapine (5.33); clozapine-N-oxide (4.18); olanzapine (5.45); thioridazine (4.91); zotepine (4.75); remoxipride (4.51) and risperidone (4.43). Three compounds were examined in a functional H3 receptor model as well. The electrically evoked tritium overflow from superfused mouse brain cortex slices, which represents quasi-physiological noradrenaline release, was not affected by N-desmethylclozapine (3.2 and 10 microM), clozapine-N-oxide (3.2-100 microM) and olanzapine (3.2-32 microM). On the other hand, the three compounds shifted to the right the concentration-response curve of histamine for its inhibitory effect on the evoked overflow; the apparent pA2 values were 5.84, 4.21 and 5.80, respectively. The present study shows that five atypical neuroleptics of different chemical classes and the two major metabolites of clozapine possess a lower affinity and/or antagonistic potency at H3 receptors than clozapine itself (pKi 6.15, pA2 6.33; Kathmann M, Schlicker E, Gothert M (1994). Psychopharmacology 116: 464-468).