Given the heterogeneity within the gamma-amino-butyric acid (GABA) receptor and transporter families, a detailed insight into the pharmacology is still relatively sparse. To enable studies of the physiological roles governed by specific receptor and transporter subtypes, a series of GABA analogues comprising five-membered nitrogen- and sulfur-containing heterocycles as amine bioisosteres were synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors and GABA transporters. The dihydrothiazole and imidazoline analogues, 5-7, displayed moderate GAT activities and GABAA receptor binding affinities in the mid-nanomolar range (K-i, 90-450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABA(A)-alpha beta gamma receptors but somewhat lower potency as partial agonists at the GABA(A)-rho(1) receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABA(A)-alpha beta gamma receptors but not the GABA(A)-rho(1) receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.

Five-Membered N-Heterocyclic Scaffolds as Novel Amino Bioisosteres at γ-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

Giraudo A.;Rolando B.;De Blasio R.;Boschi D.;Lolli M. L.;
2019

Abstract

Given the heterogeneity within the gamma-amino-butyric acid (GABA) receptor and transporter families, a detailed insight into the pharmacology is still relatively sparse. To enable studies of the physiological roles governed by specific receptor and transporter subtypes, a series of GABA analogues comprising five-membered nitrogen- and sulfur-containing heterocycles as amine bioisosteres were synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors and GABA transporters. The dihydrothiazole and imidazoline analogues, 5-7, displayed moderate GAT activities and GABAA receptor binding affinities in the mid-nanomolar range (K-i, 90-450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABA(A)-alpha beta gamma receptors but somewhat lower potency as partial agonists at the GABA(A)-rho(1) receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABA(A)-alpha beta gamma receptors but not the GABA(A)-rho(1) receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.
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http://pubs.acs.org/jmc
PHARMACOLOGICAL CHARACTERIZATION; BINDING; ANALOGS; GLUTAMATE; GLYCINE; SELECTIVITY; ANTAGONISTS; MODULATION; SUBTYPES; AGONISTS
Giraudo A.; Krall J.; Bavo F.; Nielsen B.; Kongstad K.T.; Rolando B.; De Blasio R.; Gloriam D.E.; Loffler R.; Thiesen L.; Harpsoe K.; Frydenvang K.; Boschi D.; Wellendorph P.; Lolli M.L.; Jensen A.A.; Frolund B.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1719861
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