The interaction of tertatolol (d,l-hydroxy-2'-t-butylamino-3'propyloxy-8- thiochromane HCl) with 5-hydroxytryptamine (serotonin; 5-HT) receptors in several brain areas were investigated. Both ligand binding techniques and an electrophysiological approach were used. First, the affinity of tertatolol for different 5-HT receptor subtypes was measured, as assayed by a competition binding experiment using specific ligands in several brain areas. It was found that (-)-tertatolol binds to 5-HT1 receptor subtypes in rat brain, particularly the 5-HT(1A) subtype in the hippocampus (K(i) = 5.9 nM). (-)-Tertatolol showed much lower affinity for 5-HT(1B) (K(i) = 118.4 nM), 5- HT(1C) (K(i) = 699.6 nM) and 5-HT2 (K(i) = 678.6 nM) receptors. The binding of tertatolol to hippocampal 5-HT(1A) receptors was stereospecific in that the affinity of (+)-tertatolol to these receptors (K(i) = 311.6 nM) was about 20 times lower as compared to that of (-)-tertatolol. There was no significant binding of tertatolol to 5-HT(1D), 5-HT3, alpha-1 adrenergic receptors or to the serotonin uptake site. Electrophysiological techniques were used to study the effects of (-)-tertatolol on the activity of 5-HT- containing neurons in the rat dorsal raphe nucleus. Acute i.v. injection of (-)-tertatolol caused a slight increase in the basal firing rate of the majority of 5-HT neurons studied. Pretreatment with (-)-tertatolol (1 mg/kg i.v.) significantly reduced the inhibitory effect of 8-hydroxy-2-(di-n- proylamino) tetralin (0.25-64 μg/kg i.v.) on the firing rate of dorsal raphe nucleus 5-HT neurons. These data indicate that (-)-tertatolol is an effective 5-HT(1A) receptor antagonist in the rat central nervous system.
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - 1993|
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