J. Traber

3H-TVX Q 7821: identification of 5-HT1 binding sites as target for a novel putative anxiolytic

SummaryIn order to clarify the mechanism of action of the putative nonbenzodiazepine anxiolytic TVX Q 7821 [2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3-(2H)one-1,1-dioxidehydrochloride], binding studies with the radio labelled compound were performed.3H-TVX Q 7821 bound apidly, reversibly and in a saturable manner with high affinity to calf brain structures with preference for the hippocampus (KD 1.62 nmol/l;Bmax 320 fmol/mg protein).3H-TVX Q 7821 binding was displaced only by 5-hydroxytryptamine and its agonists and antagonists including spiperone, but was not displaced by a variety of other neurotransmitters and drugs. The 5-HT2 receptor antagonist ketanserin was a weak displacer. The hippocampal binding sites for3H-TVX Q 7821 were pharmacologically very similar to the 5-HT1-binding sites in this region. TVX Q 7821 is likely to be an important tool in research on functional aspects of 5-HT1 binding sites.

5-HT1A Receptors in Anxiety

Brain 5-HT receptors have been classified in at least six subtypes (5-HT1A, 1B, 1C, 1D, 2 AND 3; Peroutka, 1988), among which the 5-HT1A subtype has been the focus of intense research during the last few years. This receptor type is located both presynaptically on the 5-HT cell bodies (somatodendritic receptors), predominantly in the dorsal and median raphe nuclei and postsynaptically, predominantly in the limbic system (Verge et al., 1985; Weissmann-Nanopoulos et al., 1985). Activation of presynaptic 5-HT1A receptors with 5-HT1A ligands inhibits serotonergic neurotransmission (Hamon et al., 1988; Hjorth and Magnusson, 1988; Sharp et al., 1989a, b) and the physiological role of these receptors is probably to provide the brain with an autoinhibitory feedback system controlling 5-HT neurotransmission. At the postsynaptic level, activation of 5-HT1A receptors results in neuronal inhibition, the consequences of which are not well understood (e.g. Sprouse and Aghajanian, 1988; Martin and Mason, 1987).

5-HT1A Receptor Partial Agonists as Anxiolytics

In the present study some biochemical and behavioral pharmacological properties of the novel pyrimidinylpiperazine anxiolytics buspirone, gepirone and ipsapirone were compared. The three compounds were identified in vitro as high affinity partial agonists at postsynaptic (hippocampal) serotonin (5-HT) 1A receptors. These results were paralled by findings in behavioral tests such as circling behavior and 5-HT syndrome, in which presumably postsynaptic 5-HT1A receptors are involved. In models where mainly presynaptic 5-HT1A receptors are involved such as drug discrimination buspirone, gepirone and ipsapirone behaved as full agonists. Anxiolytic activity was obtained with the three pyrimidinylpiperazines in several animal models including conflict and nonconflict ones. Ipsapirone was found to be unique in having a social behavior stimulating action. The present data classified buspirone, gepirone and ipsapirone as agonists and partial agonists at pre- and postsynaptic 5-HT1A receptors, respectively. The anxiolytic actions of these drugs are very likely mediated by the interactions with the 5-HT1A receptors.

Nimodipine and Nervous System Function

Nimodipine is a Ca2+ antagonist of the 1,4-dihydropyridine type that specifically blocks the L-type Ca2+ channel by reducing its opening probability. Binding sites for nimodipine are distinctly located in the central nervous system (CNS), especially in the hippocampal formation and the cortex. These brain structures play an important role in the regulation of cognitive processes. Nimodipine acts not only on neurons but also on glial cells (Hertz et al. 1989). This finding may be highly relevant for nimodipine’s action, given the fact that 50% of the cells in the CNS consist of glial cells which support and modulate the function of neurones in the CNS. Finally, there are binding sites for nimodipine on CNS blood vessels which thus provide another target for the drug.

Serotonin und Angst: Die Rolle von Serotonin1A-Rezeptoren am Beispiel von Ipsapiron

Vor ca. drei Jahrzehnten begann mit der Entdeckung der Anxiolytika vom Benzodiazepin-Typ eine neue Ara in der Psychopharmakologie (Sternbach 1973). Bis heute gelten Pharmaka dieser und einiger anderer Substanzklassen als Mittel der Wahl zur Behandlung von Angstzustanden; sie werden in groser Zahl verschrieben und dominieren das Feld der Tranquilizer und Hypnotika. Gemeinsam ist diesen Substanzen die Wechselwirkung mit spezifischen Bindungsstellen im Gehirn, den sog. Benzodiazepin-Rezeptoren. Sie sind ein Teil des GABA-Rezeptor/Cl--Ionenkanal-Komplexes. Anxiolytisch wirksame Benzodiazepine fordern die Bindung des Neurotransmitters Gamma-Aminobuttersaure (GABA) an seinen Rezeptor (GABAA-Rezeptor) und verstarken so die inhibitorische GABAerge Neurotransmission, welche mit einem vermehrten Einstrom von Cl--Ionen verbunden ist (Tallman u. Gallager 1985). Diese Forderung der GABA-Wirkung liegt auch der Anxiolyse durch Benzodiazepine zugrunde.