QSAR in Development of Antidepressants
QSAR in Development of Antidepressants QSAR in Development of Antidepressants
Treatment Past and Present • First generation – Monoamine oxidase inhibitors(MAOIs) • mechanism-based irreversible inhibitors – Tricyclic antidepressants(TCAs) • three ring molecular core • Second generation – Selective serotonin (5-HT) reuptake inhibitors(SSRIs) – Selective norepinephrine(NE) reuptake inhibitors (SNRIs) N Imipramine NH 2 Cl Cl sertaline N O N N N H H N phenelzine amoxapine NH 2
Serotonin Hypothesis • serotonergic neurotransmission in forebrain – key determinant of mood • euphoria-high activity • dyphoria-low activity • depression response to low levels • Serotonin inhibitors interfere with 5-HT activity – removes serotonin from synapse – elevating low levels of synaptic serotonin
- Page 1 and 2: The Next Generation of Antidepressa
- Page 3: Depression as a Disease • 1 out 5
- Page 7 and 8: Serotonin effect Phil Skolnick, P.
- Page 9 and 10: Project Aim • explore a faster ac
- Page 11 and 12: QSAR Design • Create training set
- Page 13 and 14: Why use GFA • builds multiple mod
- Page 15 and 16: • r 2 =.87 QSAR results • valid
- Page 17 and 18: Strategy Nh 2 fluoxetine F Cl O H N
- Page 19 and 20: Synthetic scheme S antidepressants
- Page 21 and 22: Synthetic scheme
- Page 23: References • Phil Skolnick, P. P.
Seroton<strong>in</strong> Hypothesis<br />
• serotonergic neurotransmission <strong>in</strong> forebra<strong>in</strong><br />
– key determ<strong>in</strong>ant <strong>of</strong> mood<br />
• euphoria-high activity<br />
• dyphoria-low activity<br />
• depression response to low levels<br />
• Seroton<strong>in</strong> <strong>in</strong>hibitors <strong>in</strong>terfere with 5-HT activity<br />
– removes seroton<strong>in</strong> from synapse<br />
– elevat<strong>in</strong>g low levels <strong>of</strong> synaptic seroton<strong>in</strong>
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