title: Novel benzodioxopiperazines acting as antagonists at postsynaptic 5-HT1A receptors and as agonists at 5-HT1A autoreceptors: a comparative pharmacological characterization with proposed 5-HT1A antagonists.
abstract: The novel benzodioxopiperazines [4-(benzodioxan-5-yl)1-[2- (benzocyclobutane-1-yl)ethyl]piperazine] (S 14489), [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine)] (S 15535) and [4-(benzodioxan-5-yl)1-[2(indan-1-yl)ethyl]piperazine (S15931) competitively displaced the binding of [3H]-8-OH-DPAT at serotonin (5-HT)1A receptors with affinities (pKis) of 9.2, 8.8 and 8.9, respectively. These values compared favorably with those of the structurally related eltoprazine (8.0) and the proposed 5-HT1A antagonists NAN-190 (9.2), MDL 73005 EF (8.9), SDZ 216-525 (8.8), BMY 7378 (8.7), (-)-tertatolol (8.1), (-)-alprenolol (7.7), WAY 100,135 (7.5) and spiperone (6.9). The affinities of S 14489, S 15535 and S 15931 for other 5-HT receptor types (5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3) were about 50 to 1000-fold lower. The spontaneous tail-flicks, flat-body posture and hypothermia mediated by an action of the 5-HT1A agonist 8-OH-DPAT at postsynaptic 5-HT1A receptors were dose-dependently and completely antagonized by S 14489, S 15535 and S15931 at doses of 0.63 to 10.0 and 2.5 to 40.0 mg/kg for s.c. and oral administration, respectively. They did not induce these responses alone, and in their presence, dose-response curves for 8-OH-DPAT were shifted in parallel to the right without loss of maximal effect. By contrast, eltoprazine, MDL 73005 EF, BMY 7378 and NAN-190 behaved as "partial" agonists and only incompletely antagonized the actions of 8-OH-DPAT in these tests. At 5-HT1A autoreceptors, S 14489, S 15535 and S 15931 acted as agonists in inhibiting striatal 5-hydroxytryptophan accumulation (0.16-2.5 mg/kg, s.c.) and in abolishing the electrical activity of the dorsal raphe nucleus (0.005-0.100 mg/kg, i.v.). Eltoprazine, BMY 7378, NAN-190 and MDL 73005 EF also behaved as agonists at these 5-HT1A autoreceptors, whereas WAY 100,135, spiperone, (-)-tertatolol, (-)-alprenolol and SDZ 216-525 inhibited neither accumulation nor firing. WAY 100,135 and spiperone antagonized the inhibition of DRN firing induced by S 14489, S 15535 and S 15931. The affinity of 15535 for dopamine D1 and D2 receptors, as well as for beta-, alpha 1- and alpha 2-adrenoceptors, was > 100-fold lower than its affinity for 5-HT1A receptors. Further, in vivo, at doses of 10.0 to 40.0 mg/kg, s.c., it showed minimal activity in tests of dopamine D2 (and D1) receptor-mediated activity. Similarly, in vivo, S 15535 was weakly active in a test of alpha 1-adrenoceptor-mediated activity.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Psychopharmacology, Institut de Recherches Servier, Puteaux, Paris, France.
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.forename: H
authors.initials: H
authors.lastname: Canton
authors.forename: A
authors.initials: A
authors.lastname: Gobert
authors.forename: F
authors.initials: F
authors.lastname: Lejeune
authors.forename: J M
authors.initials: JM
authors.lastname: Rivet
authors.forename: K
authors.initials: K
authors.lastname: Bervoets
authors.forename: M
authors.initials: M
authors.lastname: Brocco
authors.forename: P
authors.initials: P
authors.lastname: Widdowson
authors.forename: T
authors.initials: T
authors.lastname: Mennini
authors.forename: V
authors.initials: V
authors.lastname: Audinot
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D003432:Cross-Linking Reagents; D004146:Dioxanes / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013569:Synapses / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D004146:Dioxanes; D010879:Piperazines; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C079549:4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine; C085686:S 14489; C085687:S 15931; C063828:eltoprazine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin