Galantamine

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* 2006 Sales: $225 Million<ref>Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)</ref>
* 2006 Sales: $225 Million<ref>Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)</ref>
* Importance: Part of a newer generation of treatments for [[Alzheimer's Disease]], although no definitive proof exists as to whether it alters the progression of the disease.
* Importance: Part of a newer generation of treatments for [[Alzheimer's Disease]], although no definitive proof exists as to whether it alters the progression of the disease.
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* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
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* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders
===Mechanism of Action===
===Mechanism of Action===
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<scene name='Galantamine/Ache/1'>TextToBeDisplayed</scene>
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Galantamine is a potent [[Acetylcholinesterase]] (AChE) inhibitor to the active site of <scene name='Galantamine/Ache/1'>AChE</scene>. By inhibiting AChE, the important neurotransmitter, [[acetylcholine]], is degraded at a slower rate, helping reverse the marked decrease in neuronal function evident in [[Alzheimer's Disease]] patients. Galantamine binds to the same active site gorge as acetylcholine <scene name='Galantamine/Binding/1'>interacting with the residues</scene> Glu 199, Phe 330, Trp 84, His 440, Phe 288, PHe 290, Tyr 121, Phe 331, Gly 119, Ser 200, Gly 118, and Gly 117 to tightly bind to AChE.<ref name="Guillou">PMID:15563167</ref> These interactions, which are primarily hydrophobic and pi stacking interactions, allow Galantamine outcompete Acetylcholine for the AChE active site.
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<scene name='Galantamine/Binding/1'>TextToBeDisplayed</scene>
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Described above, <scene name='1w4l/Al/1'>Galantamine</scene> (abbreviated as <scene name='1w4l/Al/2'>GAL</scene>; <font color='red'><b>colored red</b></font>) is a CAS-binding inhibitor and it is currently used in therapy of the AD. Conjugate of GAL through the <scene name='1w4l/Al/3'>alkyl linker</scene> (8 carbons, <font color='black'><b>yellow</b></font>) with a <scene name='1w4l/Al/4'>phthalimido moiety</scene> <font color='blueviolet'><b>(blueviolet)</b></font> called '''compound 3''' has a larger affinity for AChE than that of GAL alone. This is similar to previously described cases of bivalent ligands (''e.g.'' '''(''RS'')-(±)-tacrine-(10)-hupyridone'''). A comparison between <scene name='1w4l/Comparison/1'>compound 3</scene>/''Tc''AChE ([[1w4l]]) and <scene name='1w4l/Comparison/2'>galanthamine/TcAChE</scene> structure ([[1dx6]]) shows an identical binding mode of the <font color='red'><b>GAL-moiety (transparent red)</b></font> of '''compound 3''' to that of <font color='blue'><b>GAL alone (blue)</b></font> at the CAS. A <font color='gray'><b>PEG molecule (gray)</b></font> is located at the active site of the galanthamine/''Tc''AChE structure. The alkyl linker spans the active-site gorge and the phthalimido moiety of '''compound 3''' is situated near Trp279 at the PAS. '''Compound 3''' has higher affinity to ''Tc''AChE than GAL. This can be explained by the higher number of interactions between '''compound 3''' (which interacts not only with residues within CAS but also within PAS) and ''Tc''AChE relative to GAL <ref name="Guillou">PMID:15563167</ref>.
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===Pharmacokinetics===
===Pharmacokinetics===
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{| class="wikitable" border="1" width="52%" style="text-align:center"
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<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">
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|-
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<tr>
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! colspan="7" align="center"| Aceylcholinesterase Inhibitor [[Pharmaceutical_Drugs#Pharmacokinetics_Translated|Pharmacokinetics]]<ref>PMID:17113365</ref><ref>PMID: 19935404</ref><ref>PMID:7605915</ref><ref>PMID:1404819</ref><ref>doi:10.1053/cp.1999.v66.103404001</ref><ref>doi:10.1038/sj.clpt.6100242</ref><ref>PMID:12734391</ref><ref>PMID: 11741490</ref>
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<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
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|-
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<div style="height:100%; width: 100%">
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! Parameter
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{{:Acetylcholinesterase Inhibitor Pharmacokinetics}}
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! [[Donepezil]]
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</div>
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! [[Tacrine]]
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</td>
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! [[Rivastigmine]]
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</tr>
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! [[Galantamine]]
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</table>
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|-
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! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
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! 3.6
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! 1.5
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! .3
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! 1.2
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|-
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! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
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! 6.5
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! 15.7
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! 29.3
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! 42.6
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|-
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! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
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! 100
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! 17
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! 36
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! 100
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|-
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! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
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! 96
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! 55
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! 40
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! 10
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|-
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! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
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! 70
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! 3
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! 5
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! 7.3
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|-
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! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
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! 380
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! 80.4
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! 191
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! 427
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|-
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! [[Pharmaceutical_Drugs#Inhibitory_Concentration_.28IC50.29|IC<sub>50</sub>]] (nM)
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! 6.7 <br/>(Rat)
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! 450 <br/>(Human)
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! 1535 <br/>(Human)
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! 1995 <br/>(Rat)
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|-
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! Dosage (mg)
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! 5
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! 160
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! 6
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! 8
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|-
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! Metabolism
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! Hepatic (CYP2D6 & CYP3A4) & Cholinesterase
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! Hepatic (CYP1A2) & Cholinesterase
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! Cholinesterase
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! Hepatic (CYP3A4 & CYP2D6) & Cholinesterase
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|}
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===References===
===References===

Current revision

Galantamine, also known as Razadyne

Drag the structure with the mouse to rotate

Better Known as: Razadyne

  • Marketed By: Ortho Mcneil Janssen Pharmaceuticals (Subsidiary of Johnson & Johnson)
  • Major Indication: Alzheimer's Disease
  • Drug Class: Acetylcholinesterase Inhibitor
  • Date of FDA Approval (Patent Expiration): 2001 (2008)
  • 2006 Sales: $225 Million[1]
  • Importance: Part of a newer generation of treatments for Alzheimer's Disease, although no definitive proof exists as to whether it alters the progression of the disease.
  • See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Galantamine is a potent Acetylcholinesterase (AChE) inhibitor to the active site of . By inhibiting AChE, the important neurotransmitter, acetylcholine, is degraded at a slower rate, helping reverse the marked decrease in neuronal function evident in Alzheimer's Disease patients. Galantamine binds to the same active site gorge as acetylcholine Glu 199, Phe 330, Trp 84, His 440, Phe 288, PHe 290, Tyr 121, Phe 331, Gly 119, Ser 200, Gly 118, and Gly 117 to tightly bind to AChE.[2] These interactions, which are primarily hydrophobic and pi stacking interactions, allow Galantamine outcompete Acetylcholine for the AChE active site.

Pharmacokinetics

Acetylcholinesterase Inhibitor Pharmacokinetics
Parameter Donepezil Tacrine Rivastigmine Galantamine
Tmax (hr) 3.6 1.5 .3 1.2
Cmax (ng/ml) 6.5 15.7 29.3 42.6
Bioavailability (%) 100 17 36 100
Protein Binding (%) 96 55 40 10
T1/2 (hr) 70 3 5 7.3
AUC (ng/ml/hr) 380 80.4 191 427
IC50 (nM) 6.7
(Rat) 		450
(Human) 		1535
(Human) 		1995
(Rat)
Dosage (mg) 5 160 6 8
Metabolism Hepatic (CYP2D6 & CYP3A4) & AChE Hepatic (CYP1A2) & AChE AChE Hepatic (CYP3A4 & CYP2D6) & AChE

For Pharmacokinetic Data References, see: References

References

  1. ↑ Irena Melnikova, Therapies for Alzheimer's disease, Nature Reviews Drug Discovery 6, 341-342 (May 2007)
  2. ↑ Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL. The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design. J Am Chem Soc. 2004 Dec 1;126(47):15405-11. PMID:15563167 doi:http://dx.doi.org/10.1021/ja0466154


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