Antidepressant-like activity of compounds with varying efficacy at 5-HT1A receptors.
Three novel compounds (WY-48,723, WY-50,324, WY-47,846 [zalospirone]), with high affinity but varying efficacy for the 5-HT1A receptor, were examined for producing the 5-HT behavioral syndrome and for potential antidepressant activity in the forced swimming test (FST). WY-50,324 was more potent than WY-48,723 at producing the 5-HT syndrome, but unlike WY-48,723, it produced only some of the behaviors of the 5-HT syndrome and its profile resembles that of a partial agonist. WY-48,723 appeared to be a full agonist because it produced behavioral effects similar to those of 8-OH-DPAT. The syndrome produced by these compounds was antagonized by pretreatment with pindolol. Zalospirone did not produce the syndrome but it antagonized the syndrome produced by 8-OH-DPAT. WY-48,723 and WY-50,324 reduced immobility time in the FST. These effects were similar to those produced by the tricyclic antidepressant desipramine and the 5-HT1A agonist 8-OH-DPAT. Zalospirone did not reduce immobility time, but increased it, which made it difficult to evaluate in this screen. These results suggest that the full agonist WY-48,723 and the partial agonist WY-50,324 may both possess antidepressant activity. Antidepressant-like activity appears to be a characteristic of compounds with a medium to high efficacy for activating 5-HT1A receptors.
Singh
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A
Department of Psychiatry, University of Pennsylvania, Philadelphia 19104-2649.
Lucki
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I
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054833:Isoindoles; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists; D013550:Swimming
D000928:Antidepressive Agents; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C067729:zalospirone; C081272:WY 50324; C081273:WY 48723; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin