- Y Aminobutyric Acid Gaba Is One Of The Most Important Neurotransmitters In Mammalian Systems And It Is Mainly Expresse 1 (183.99 KiB) Viewed 40 times
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Y-Aminobutyric acid (GABA) is one of the most important neurotransmitters in mammalian systems and it is mainly expressed in the brain. There are several classes of GABA receptors (GABAA, GABAB and GABAC). L-Baclofen is a GABAB receptor agonist and has been used for treatment of muscle spasticity, including in multiple sclerosis patients. In contrast, gabazine is a GABAB receptor antagonist and thus blocks the effect of GABA and other agonists at GABAB receptors. CI i) ii) iii) iv) H₂N. CO,H GABA H₂N CO₂H L-baclofen Br NH₂ gabazine CO₂H Using structures to aid your explanation, suggest why L-baclofen is an agonist of GABAB receptors and gabazine is an antagonist. (4 marks) Site-directed mutagenesis and modelling studies have identified that the amino acid residues of serine, tyrosine and aspartic acid are important for the binding of GABA and L-baclofen into the GABAB receptor binding site. Suggest the likely binding interactions (e.g. hydrogen bonding, ion-dipole interactions, etc) that would occur at physiological pH between L-baclofen and these amino acid residues. For full marks clearly show the binding interactions and use lone pairs of electrons, full charges and 8 and 8 where appropriate. (6 marks) L-Baclofen is up to 5 times more effective therapeutically than its racemate (equal mix of L- and D-enantiomers). Draw the structure of the D-enantiomer and suggest why the stereochemistry of baclofen is so important to its effectiveness as an agonist. (2 marks) By comparing the structures of GABA and L-baclofen, suggest why GABA has very low oral bioavailability and why L-baclofen can be taken orally and ultimately can enter the central nervous system. (3 marks)