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.
Scott
Claire
C
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.
Soffin
Ellen M
EM
Hill
Matthew
M
Atkinson
Peter J
PJ
Langmead
Christopher J
CJ
Wren
Paul B
PB
Faedo
Stefania
S
Gordon
Laurie J
LJ
Price
Gary W
GW
Bromidge
Steve
S
Johnson
Christopher N
CN
Hagan
James J
JJ
Watson
Jeannette
J
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