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Structural Determinants for AMPA Agonist Activity of Aryl or Heteroaryl Substituted AMPA Analogues. Synthesis and Pharmacology
Author(s) -
Sørensen Ulrik S.,
Falch Erik,
Stensbøl Tine B.,
Jaroszewski Jerzy W.,
Madsen Ulf,
KrogsgaardLarsen Povl
Publication year - 2001
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(200102)334:2<62::aid-ardp62>3.0.co;2-g
Subject(s) - ampa receptor , chemistry , agonist , stereochemistry , chemical synthesis , receptor , glutamate receptor , biochemistry , in vitro
We have previously reported the synthesis and pharmacological characterization of analogues of 2‐amino‐3‐(3‐hydroxy‐5‐methyl‐4‐isoxazolyl)propionic acid (AMPA, 1a ), in which the methyl group was replaced by a phenyl group (APPA, 1b ) or heteroaryl groups. While 2b and its 3‐pyridyl analogue 2‐amino‐3‐[3‐hydroxy‐5‐(3‐pyridyl)‐4‐isoxazolyl]propionic acid (3‐Py‐AMPA, 3 ) show very low affinity for AMPA receptors, introduction of heteroaryl substituents containing heteroatom in the 2‐position provides potent AMPA receptor agonists. We here report the synthesis and pharmacology of 2‐amino‐3‐(3‐hydroxy‐5‐pyrazinyl‐4‐isoxa‐zolyl) propionic acid ( 7 ) (IC 50 = 1.2 μM; EC 50 = 11 μM), which is weaker as an AMPA agonist than AMPA (IC 50 = 0.040 μM; EC 50 = 3.5 μM) but comparable in potency with 2‐Py‐AMPA ( 4 ) (IC 50 = 0.57 μM; EC 50 = 7.4 μM), as determined in radioligand binding and electrophysiological experiments, respectively. The AMPA analogues 8a—c , containing 2‐, 3‐, or 4‐methoxyphenyl substituents, respectively, and the corresponding hydroxyphenyl analogues, 9a—c , were also synthesized and evaluated pharmacologically. With the exception of 2‐amino‐3‐[3‐hydroxy‐5‐( 2‐hydroxyphenyl)‐4‐isoxazolyl]propionic acid ( 9a ), which is a very weak AMPA agonist (IC 50 = 45 μM; EC 50 = 324 μM), none of these compounds showed detectable effect at AMPA receptors.