A series of ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) analogues were evaluated for activity at homo-oligomeric glutamate 1 -flop (Glu 1 -flop) receptors expressed in Xenopus oocytes, using the two-electrode voltage clamp technique. ( RS )-2-Amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) (EC 50 , 2.4 μM), a homologue of AMPA having a carboxyl group as the terminal acidic functionality, was five times more potent than AMPA (EC 50 , 12 μM) and 20 times more potent than kainate (EC 50 , 46 μM). ( RS )-2-Amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (Tri-F-AMPA), in which an electronegative trifluoromethyl group is substituted for the methyl group on the isoxazole ring in the AMPA structure, was three times more potent than AMPA, whereas ( RS )-3-hydroxy-4,5,6,7-tetrahydroisoxazolo(5,4- c )pyridine-5-carboxylic acid (5-HPCA), a bicyclic analogue of AMPA with highly restricted conformational flexibility was 10 times less potent than AMPA. The limiting slope of log-log plots of Glu 1 -flop receptor currents versus low agonist concentrations had a value of 1.7 for ACPA and kainate compared to 1.5 for Tri-F-AMPA and 1.3 for 5-HPCA and AMPA. The amplitude of responses evoked by near saturating concentrations of the agonists varied more than 7-fold. The sequence of efficacy was ACPA = kainate > Tri-F-AMPA > AMPA > 5-HPCA. Moreover, when saturating concentrations of Tri-F-AMPA and kainate were co-applied, the response was significantly greater than when each of the agonists was applied separately. The potency of the antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo( f )quinoxaline (NBQX) (estimated K B , ∼ 200 nM), to block currents mediated by Glu 1 -flop receptors was similar for all of the agonists tested in this study. These results indicate that relatively minor changes in the molecular structure of AMPA are associated with marked effects on potency and efficacy. In particular, it is suggested that the acidity of the terminal group plays a major role in determining the degree of receptor activation in the steady state.
European Journal of Pharmacology – Elsevier
Published: Jul 18, 1996
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera