Biomedical Engineering Reference
In-Depth Information
COOH
COOH
COOH
H 2 N
H 2 N
H 2 N
COOH
COOH
COOH
( S )-4CPG ( 15.101 )
( S )-M4CPG ( 15.102 )
(+)-4C2MPG ( 15.103 )
COOH
H 2 O 3 P
COOH
NH 2
COOH
HOOC
HOOC
NH 2
NH 2
H
MAP4 ( 15.104 )
MCCGI ( 15.105 )
(2 S ,4 S )-Me-Glu ( 15.106 )
COOH
HOOC
NH 2
COOH
H
HOOC
O
NH 2
H
COOH
HOOC
NH 2
( 15.107 )
( 15.108 )
LY341495 ( 15.109 )
FIGURE 15.21
Structures of some mGluR ligands.
compounds of this type is LY341495 ( 15.109 ) with a xanthylmethyl substituent. However LY341495
( 15.109 ) also shows afi nity for other subtypes, especially mGluR8 (Figure 15.21).
It can be concluded that in their antagonized state receptors from all three mGluR groups can
accommodate quite large and lipophilic side chains in a variety of positions. Furthermore, compared
with small
substituents such as methyl groups which most often confer antagonists with reduced
potency, the large “l yswatter” substituents in most cases confer antagonists with increased potency.
α
15.8.3 A LLOSTERIC M ODULATORS OF M ETABOTROPIC G LUTAMATE R ECEPTORS
CPCCOEt ( 15.110 ) is a nonamino acid compound with no structural similarity with Glu and acts as a
noncompetitive group I-selective antagonist at the 7TM region rather than the agonist-binding site. A
number of other nonamino acid mGluR antagonists have been discovered, e.g., BAY36-7620 ( 15.111 )
and EM-TBPC ( 15.112 ) which are potent mGluR1 specii c antagonists acting at the 7TM domain.
The two compounds SIB-1893 ( 15.113 ) and MPEP ( 15.114 ) have been reported to be potent and
selective, noncompetitive antagonists at mGluR5. Like CPCCOEt ( 15.110 ), MPEP ( 15.114 ) has been
shown to act at the 7TM region rather than the agonist-binding site. MPEP ( 15.114 ) also antagonizes
NMDA receptors with low micromolar potency, which has led to the design of the analog MTEP
( 15.115 ), which is slightly more potent than 15.114 as an antagonist at mGluR5 and with no NMDA
antagonist activity. SIB-1893 ( 15.113 ) and MPEP ( 15.114 ) also act as positive allosteric modulators
at mGluR4. The allosteric effect is dependent upon Glu activation, and the compounds are thus
unable to activate the mGluR4 receptor directly. Instead, the compounds enhance the response
mediated by Glu, causing a leftward shift of concentration-response curves and an increase in the
maximum response (Figure 15.22).
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