New methoxy-chroman derivatives, 4[N-(5-methoxy-chroman-3-yl)N- propylamino]butyl-8-azaspiro-(4,5)-decane-7,9-dione [(+/-)-S 20244] and its enantiomers, (+)-S 20499 and (-)-S 20500, with potent agonist properties at central 5-hydroxytryptamine1A receptors.
The potential interaction of the new methoxy-chroman derivatives: (+/-)-S 20244 (4-[N-(5-methoxy-chroman-3-yl)N-propylamino]butyl-8-azaspiro- (4,5)-decane-7,9-dione) and its enantiomers (+)-S 20499 and (-)-S 20500 with central 5-hydroxytryptamine1A (5-HT1A) receptors was assessed using biochemical and electrophysiological tests in the rat. 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). As seen with the prototypical 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin, (+/-)-S 20244, (+)-S 20499 and (-)-S 20500 inhibited forskolin-activated adenylate cyclase in hippocampal homogenates with potencies corresponding to their respective affinities for 5-HT1A sites. The maximal inhibitory effect of the chroman derivatives was not additive with that of 8-hydroxy-2-(di-n- propylamino)tetralin and could be competitively reduced by 5-HT1A antagonists such as (-)-propranolol and (+/-)-tertatolol. Electrophysiological recordings within the dorsal raphe nucleus both in vitro (in brain-stem slices) and in vivo (in chloral hydrate anesthetized rats) showed that (+)-S 20499, (+/-)-S 20244 and (-)-S 20500 induced, in that order of (decreasing) potency, a dose-dependent reduction in the spontaneous firing of serotoninergic neurons. In vitro, as well as in vivo, the inhibitory influence of the chroman derivatives on the discharge frequency of serotoninergic neurons could be competitively antagonized by (+/-)-tertatolol. Finally, oral administration of increasing doses of the most potent enantiomer, (+)-S 20499, induced a marked reduction in the rate of 5-HT turnover, without affecting that of dopamine, in various brain areas. All these biochemical and electrophysiological data indicate that (+)-S 20499 is a highly potent agonist at both presynaptic (i.e., somatodendritic) and postsynaptic 5-HT1A receptors in the rat brain.
Kidd
E J
EJ
INSERM U288, Neurobiologie Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Haj-Dahmane
S
S
Jolas
T
T
Lanfumey
L
L
Fattaccini
C M
CM
Guardiola-Lemaitre
B
B
Gozlan
H
H
Hamon
M
M
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013237:Stereoisomerism
D014151:Anti-Anxiety Agents; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; D012701:Serotonin; C075319:alnespirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases; D004298:Dopamine