SB-649915, a novel, potent 5-HT1A and 5-HT1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue.
An increase in brain 5-HT levels is thought to be the key mechanism of action which results in an antidepressant response. It has been proven that selective serotonin re-uptake inhibitors are effective antidepressants but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptor desensitisation. Therefore an agent incorporating 5-HT re-uptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast acting clinical agent. The current studies describe the in vitro profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound which has high affinity for human recombinant 5-HT1A, 5-HT1B and 5-HT1D receptors (pKi values of 8.6, 8.0, 8.8, respectively) and the human recombinant 5-HT transporter (pKi value of 9.3). SB-649915 also displays high affinity for rat, guinea pig, mouse and marmoset native tissue 5-HT1A, 5-HT1B and 5-HT1D receptors and rat native tissue 5-HT transporters (pKi values>or=7.5). In functional [35S]GTPgammaS binding studies, SB-649915 (up to 1 microM) does not display intrinsic activity in HEK293 cells expressing human recombinant 5-HT1A receptors but acts as a partial agonist at human recombinant 5-HT1B and 5-HT1D receptors with intrinsic activity values of 0.3 and 0.7, respectively, as compared to the full agonist 5-HT. From Schild analysis, SB-649915 caused a concentration-dependent, rightward shift of 5-HT-induced stimulation of basal [35S]GTPgammaS binding in cells expressing human recombinant 5-HT1A or 5-HT1B receptors to yield pA2 values of 9.0 and 7.9, respectively. In electrophysiological studies in rat dorsal raphe nucleus, SB-649915 did not affect the cell firing rate up to 1 microM but attenuated (+)8-hydroxy-2-(di-n-propylamino) tetralin-induced inhibition of cell firing with an apparent pKb value of 9.5. SB-649915 (1 microM) significantly attenuated exogenous 5-HT-induced inhibition of electrically-stimulated [3H]5-HT release from guinea pig cortex. In studies designed to enhance endogenous 5-HT levels, and therefore increase tone at 5-HT1B autoreceptors, SB-649915 significantly potentiated [3H]5-HT release at 100 and 1000 nM. In LLCPK cells expressing human recombinant 5-HT transporters and in rat cortical synaptosomes, SB-649915 inhibited [3H]5-HT re-uptake with pIC50 values of 7.9 and 9.7, respectively. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue systems and represents a novel mechanism that could offer fast acting antidepressant action.
Psychiatry and Neurology and GI Centres of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW and Via Fleming 4, Verona, Italy.
Claire
C
Scott
Ellen M
EM
Soffin
Matthew
M
Hill
Peter J
PJ
Atkinson
Christopher J
CJ
Langmead
Paul B
PB
Wren
Stefania
S
Faedo
Laurie J
LJ
Gordon
Gary W
GW
Price
Steve
S
Bromidge
Christopher N
CN
Johnson
James J
JJ
Hagan
Jeannette
J
Watson
D000818:Animals; D017660:Autoreceptors / Q000819:agonists / Q000037:antagonists & inhibitors; D048588:Benzoxazines; D001667:Binding, Competitive / Q000187:drug effects; D002144:Callithrix; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics; D044346:Receptor, Serotonin, 5-HT1D / Q000235:genetics; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D017660:Autoreceptors; D048588:Benzoxazines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010880:Piperidines; D011804:Quinolines; D044282:Receptor, Serotonin, 5-HT1A; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011994:Recombinant Proteins; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C511971:SB-649915