RT Journal Article
SR Electronic
T1 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.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 863
OP 872
VO 264
IS 2
A1 E J Kidd
A1 S Haj-Dahmane
A1 T Jolas
A1 L Lanfumey
A1 C M Fattaccini
A1 B Guardiola-Lemaitre
A1 H Gozlan
A1 M Hamon
YR 1993
UL http://jpet.aspetjournals.org/content/264/2/863.abstract
AB 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.