title: SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test.
abstract: Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (+/-) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT(1A/B) receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED(50) of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [(3)H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (p<0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.
authors.affiliation: Schizophrenia and Bipolar Research, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Essex CM19 5AW, UK.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Starr
authors.forename: Gary W
authors.initials: GW
authors.lastname: Price
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Watson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Atkinson
authors.forename: Roberto
authors.initials: R
authors.lastname: Arban
authors.forename: Sergio
authors.initials: S
authors.lastname: Melotto
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Mark S
authors.initials: MS
authors.lastname: Duxon
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D048588:Benzoxazines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002144:Callithrix; D004357:Drug Synergism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017374:Paroxetine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012919:Social Behavior; D014828:Vocalization, Animal / Q000187:drug effects / Q000502:physiology
chemical_list: D014151:Anti-Anxiety Agents; D048588:Benzoxazines; D017374:Paroxetine; D010880:Piperidines; D011804:Quinolines; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C511971:SB-649915