Abstract
A series of new 3-[4-(4-arylpiperazinyl)-butyl]-beta-tetralonohydantoins (8a-13a) were synthesized. The compounds exhibited high affinity for 5-HT(1A) receptors (K(i)=6 to 55 nM) combined with moderate-to-high 5-HT(2A) receptor affinities (K(i)=45 to 213 nM). The results of in vivo studies indicated that of the compounds tested, 3-[4-(4-phenylpiperazinyl)-butyl-beta-tetralonohydantoin (8a) showed features of full (pre- and postsynaptic) 5-HT(1A) receptor agonists, whereas compounds 9a-13a behaved like antagonists of postsynaptic 5-HT(1A) receptors; additionally, compound 13a produced an effect characteristic of presynaptic 5-HT(1A) receptor agonists. Moreover, compounds 8a and 10a-13a exhibited properties of 5-HT(2A) receptor antagonists. Due to the most interesting 5-HT(1A)/5-HT(2A) functional profile compounds 8a and 13a were further tested for their potential psychotropic activity. In fact, compound 8a (but not 13a) showed diazepam-like anxiolytic activity and behaved like a weak antidepressant.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Anxiety Agents / chemical synthesis
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Anti-Anxiety Agents / chemistry
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Anti-Anxiety Agents / pharmacology
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Antidepressive Agents / chemical synthesis
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Antidepressive Agents / chemistry
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Antidepressive Agents / pharmacology
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Drug Evaluation, Preclinical
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Hydantoins / chemical synthesis*
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Hydantoins / chemistry*
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Mice
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Rats
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Receptor, Serotonin, 5-HT1A / drug effects
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Receptor, Serotonin, 5-HT1A / metabolism*
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Receptor, Serotonin, 5-HT2A / drug effects
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Receptor, Serotonin, 5-HT2A / metabolism*
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology
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Serotonin Receptor Agonists / chemical synthesis*
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Serotonin Receptor Agonists / chemistry
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Serotonin Receptor Agonists / pharmacology
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Structure-Activity Relationship
Substances
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Anti-Anxiety Agents
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Antidepressive Agents
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Hydantoins
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Receptor, Serotonin, 5-HT2A
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Serotonin Antagonists
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Serotonin Receptor Agonists
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Receptor, Serotonin, 5-HT1A