DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

receptors are found in the retina, spinal cord, superior colliculus, and
pituitary (Olsen and Betz, 2005).
Glycine. Many of the features described for the GABA A
receptor family
also apply to the inhibitory glycine receptor, which is prominent
in the brainstem and spinal cord. Multiple subunits assemble into a
variety of glycine receptor subtypes. These pharmacological subtypes
are detected in brain tissue with particular neuroanatomical
and neurodevelopmental profiles. As with the GABA A
receptor, the
complete functional significance of glycine receptor subtypes is not
known. There is evidence for clustering of glycine receptors by the
anchoring protein gephyrin (Sola et al., 2004). An additional role for
glycine is as a co- agonist at NMDA receptors, at which both glutamate
and glycine must be present for activation to occur.
Glutamate and Aspartate. Glutamate and aspartate are found in very
high concentrations in brain, and both amino acids have powerful
excitatory effects on neurons in virtually every region of the CNS.
Their widespread distribution initially obscured their roles as transmitters,
but there now is broad acceptance that glutamate and possibly
aspartate are the principal fast (“classical”) excitatory
transmitters throughout the CNS (Bleich et al., 2003; Conn, 2003).
Multiple subtypes of receptors for excitatory amino acids have been
cloned, expressed, and characterized pharmacologically, based on
the relative potencies of synthetic agonists and the discovery of
potent and selective antagonists (Kotecha and MacDonald, 2003).
Glutamate receptors are classed functionally either as ligand- gated
ion channel (“ionotropic”) receptors or as “metabotropic” GPCRs
(Table 14–3).
Neither the precise number of subunits t hat assembles to generate
a functional glutamate ionotropic receptor ion channel in vivo nor
the intramembranous topography of each subunit has been established
unequivocally. The ligand- gated ion channels are further classified
according to the identity of agonists that selectively activate each receptor
subtype, and are broadly divided into N-methyl-D-aspartate
Table 14–3
Classification of Glutamate and Aspartate Receptors a
FUNCTIONAL GENE
CLASSES FAMILIES AGONISTS ANTAGONISTS
Ionotropic
AMPA GluR1, 2, 3, 4 AMPA CNQX
Kainate
NBQX
(s) -5-fluorowillardine GYK153655
Kainate GluR5, 6, 7 Kainate CNQX
KA1, 2 ATPA LY294486
NMDA NR1, 2A, 2B, 2C, 2D Aspartate D-AP5
NMDA
2R-CPPene
MK-801
Ketamine
Phencyclidine
D-aspartate
INTRACELLULAR
Metabotropic
SIGNALING
Group 1 mGluR1 3,5-DHPG, quisqalate AIDA a G i
-PLC-IP 3
-Ca 2+
mGluR5
CBPG
Group2 mGluR2 APDC, MGS0028 EGLU a G i
-AC (b cAMP)
mGluR3 DCG-IV, LY354740 PCCG-4
Group3 mGluR4 L-AP-4 MAP4 a G i
-AC (b cAMP)
mGluR6 L-AP4 MPPG
mGluR7 L-AP4 LY341495
mGluR8
L-AP4, (S)-3,4-DCPG
a
Glutamate is the principal agonist at both ionotropic and Metabotropic receptors for glutamate and aspartate.
CNQX, 6-Cyano-7-nitroquinoxaline-2,3-dione; NBQX, 1,2,3,4-Tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide; D-AP5, D-2-
amino-5-phosphonovaleric acid; AIDA, 1-aminoindan-1,5-dicarboxylic acid; CBPG, (S)-(+)-2-(3′-carboxybicyclo(1.1.1)pentyl)-glycine; EGLU,
(2S)-α-ethylglutamic acid; PCCG-4, phenylcarboxycyclopropylglycine; MAP4, (S)-amino-2-methyl-4-phosphonobutanoic acid; MPPG, (RS)-amethyl-4-phosphonophenylglycine;
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, 2-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic
acid; NMDA, N-methyl-D-aspartate; 3,5-DHPG, 3,5-dihydroxyphenylglycine; DCG-IV, dicarboxycyclopropyl)glycine; L-AP-4,
L-2-amino-4-phosphonobutiric acid; (S)-3,4-DCPG, (S)-3,4-dicarboxyphenylglycine.