Psychiatry related information on 8-[4-[(5-methoxychroman-3-yl)-propyl-amino]butyl]-8-azaspiro[4.5]decane-7,9-dione

• Given the therapeutic potential of selective 5-HT1A agonists in the treatment of affective disorders, we have examined the changes in 5-HT1A receptors induced by 2-week minipump administration of alnespirone (0.3 and 3 mg/kg/day) and 8-OH-DPAT (0.1 and 0.3 mg/kg/day) [1].
• However, in terms of selectivity of the antiaggressive effects as determined by the absence of decrements in social interest and general motor activity, alnespirone appeared to be superior [2].
• Antidepressant-like effects of alnespirone (S 20499) in the learned helplessness test in rats [3].
• Like buspirone, alnespirone may have useful effects in the treatment of anxiety disorders [4].

High impact information on 8-[4-[(5-methoxychroman-3-yl)-propyl-amino]butyl]-8-azaspiro[4.5]decane-7,9-dione

• Autoradiographic analysis revealed a significant reduction of [3H]8-OH-DPAT and [3H]WAY-100635 (3H-labeled N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexa necarboxamide x 3HCl¿ binding to somatodendritic 5-HT1A receptors (but not to postsynaptic 5-HT1A receptors) of rats pretreated with alnespirone but not with 8-OH-DPAT [1].
• The treatment with alnespirone did not modify baseline 5-HText but significantly attenuated the ability of 0.3 mg/kg s.c. alnespirone to reduce 5-HText in the dorsal raphe nucleus (DRN) and frontal cortex [1].
• Differential regulation of somatodendritic serotonin 5-HT1A receptors by 2-week treatments with the selective agonists alnespirone (S-20499) and 8-hydroxy-2-(Di-n-propylamino)tetralin: microdialysis and autoradiographic studies in rat brain [1].
• Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (-)S 20500 [5].
• The effects of three chemically dissimilar 5-HT1A agonists administered s.c. [8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), gepirone, and (+)4-[n-5-(methoxychroman-3-yl)n-propylamino]butyl-8-azaspiro++ +[4,5] decane-7,adione ((+) S-20499)] on both of these responses were studied [6].

Biological context of 8-[4-[(5-methoxychroman-3-yl)-propyl-amino]butyl]-8-azaspiro[4.5]decane-7,9-dione

• However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses [7].
• Although it did not decrease the mean apparent affinity constant, the longer spacer improved antibody specificity by decreasing cross-reactions towards dealkylated S 20499 derivatives [8].
• S-20499 (1 mg/kg i.p.) also reduced blood pressure and heart rate within 10 min, suggesting reduced sympathetic output [9].

Anatomical context of 8-[4-[(5-methoxychroman-3-yl)-propyl-amino]butyl]-8-azaspiro[4.5]decane-7,9-dione

• In vitro binding assays revealed that these drugs bound with high affinity to 5-HT1A sites in hippocampal membranes (Ki: 0.19 nM for (+)-S 20499, 0.95 nM for (-)-S 20500 and 0.35 nM for the racemate (+/-) S 20244) [10].
• In vivo comparison of two 5-HT1A receptors agonists alnespirone (S-20499) and buspirone on locus coeruleus neuronal activity [11].
• Subjects treated with 0.5 mg/kg of 8-OH-DPAT and 10 mg/kg of (+) S-20499 displayed in the initial time period "ballistic-type" rapid forelimb movements targeted toward the side of the head [12].

Associations of 8-[4-[(5-methoxychroman-3-yl)-propyl-amino]butyl]-8-azaspiro[4.5]decane-7,9-dione with other chemical compounds

• (+) S-20499 displayed a 10(-8) M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors [7].
• The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] décane-7,9 dione), is a high affinity full 5-HT1A agonist [7].
• In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections [7].
• Immunoassays were studied as an alternative to HPLC methods for the stereoselective determination of a chiral drug, S 20499, a new anxiolytic compound that is chemically related to buspirone [8].
• To test this hypothesis, first, the 5-HT1A agonist alnespirone and gamma aminobutyric acid-A agonist muscimol were administered into the dorsal raphe nucleus [13].

Gene context of 8-[4-[(5-methoxychroman-3-yl)-propyl-amino]butyl]-8-azaspiro[4.5]decane-7,9-dione

• S-20499 also reduced plasma prolactin concentration, and did not alter plasma renin activity [9].
• Some data suggest that alnespirone might also be a weak dopamine D2 receptor agonist: it displays moderate affinity for dopamine D2 receptors in vitro and it inhibits prolactin release and induces yawning in rats [14].
• In these animals, the striatal 5-HIAA/5-HT ratio was decreased by 5 to 40 mg/kg alnespirone, whereas the striatal HVA/DA ratio was unaffected at all tested doses of alnespirone [14].
• These studies suggest that 5-HT1A receptor mechanisms mediate the effect of alnespirone on the secretion of oxytocin [15].

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