Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

Alessandro Giraudo; Jacob Krall; Francesco Bavo; Birgitte Nielsen; Kenneth Thermann Kongstad; Barbara Rolando; Rosella De Blasio; David E Gloriam; Rebekka Löffler; Louise Thiesen; Kasper Harpsøe; Karla Frydenvang; Donatella Boschi; Petrine Wellendorph; Marco L Lolli; Anders A. Jensen; Bente Frølund

doi:10.1021/acs.jmedchem.9b00026

Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

Alessandro Giraudo, Jacob Krall, Francesco Bavo, Birgitte Nielsen, Kenneth Thermann Kongstad, Barbara Rolando, Rosella De Blasio, David E Gloriam, Rebekka Löffler, Louise Thiesen, Kasper Harpsøe, Karla Frydenvang, Donatella Boschi, Petrine Wellendorph, Marco L Lolli, Anders A. Jensen, Bente Frølund

7 Citations (Scopus)

Abstract

Given the heterogeneity within the γ-aminobutyric 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 GABA_A 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-αβγreceptors but somewhat lower potency as partial agonists at the GABA_A-ρ₁ receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABA_A-αβγreceptors but not the GABA_A-ρ₁ receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	12
Pages (from-to)	5797-5809
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00026
Publication status	Published - 27 Jun 2019

Access to Document

10.1021/acs.jmedchem.9b00026

Cite this

Giraudo, A., Krall, J., Bavo, F., Nielsen, B., Kongstad, K. T., Rolando, B., De Blasio, R., Gloriam, D. E., Löffler, R., Thiesen, L., Harpsøe, K., Frydenvang, K., Boschi, D., Wellendorph, P., Lolli, M. L., Jensen, A. A., & Frølund, B. (2019). Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters. Journal of Medicinal Chemistry, 62(12), 5797-5809. https://doi.org/10.1021/acs.jmedchem.9b00026

Giraudo, A, Krall, J, Bavo, F, Nielsen, B , Kongstad, KT, Rolando, B, De Blasio, R, Gloriam, DE, Löffler, R, Thiesen, L , Harpsøe, K , Frydenvang, K, Boschi, D, Wellendorph, P, Lolli, ML, Jensen, AA & Frølund, B 2019, 'Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters', Journal of Medicinal Chemistry, vol. 62, no. 12, pp. 5797-5809. https://doi.org/10.1021/acs.jmedchem.9b00026

@article{f7fe439a35f94f9583bb0ffb2c910fdb,

title = "Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters",

abstract = "Given the heterogeneity within the γ-aminobutyric 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 GABAA 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 (Ki, 90-450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABAA-αβγreceptors but somewhat lower potency as partial agonists at the GABAA-ρ1 receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABAA-αβγreceptors but not the GABAA-ρ1 receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.",

author = "Alessandro Giraudo and Jacob Krall and Francesco Bavo and Birgitte Nielsen and Kongstad, {Kenneth Thermann} and Barbara Rolando and {De Blasio}, Rosella and Gloriam, {David E} and Rebekka L{\"o}ffler and Louise Thiesen and Kasper Harps{\o}e and Karla Frydenvang and Donatella Boschi and Petrine Wellendorph and Lolli, {Marco L} and Jensen, {Anders A.} and Bente Fr{\o}lund",

year = "2019",

month = jun,

day = "27",

doi = "10.1021/acs.jmedchem.9b00026",

language = "English",

volume = "62",

pages = "5797--5809",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "12",

}

TY - JOUR

T1 - Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

AU - Giraudo, Alessandro

AU - Krall, Jacob

AU - Bavo, Francesco

AU - Nielsen, Birgitte

AU - Kongstad, Kenneth Thermann

AU - Rolando, Barbara

AU - De Blasio, Rosella

AU - Gloriam, David E

AU - Löffler, Rebekka

AU - Thiesen, Louise

AU - Harpsøe, Kasper

AU - Frydenvang, Karla

AU - Boschi, Donatella

AU - Wellendorph, Petrine

AU - Lolli, Marco L

AU - Jensen, Anders A.

AU - Frølund, Bente

PY - 2019/6/27

Y1 - 2019/6/27

N2 - Given the heterogeneity within the γ-aminobutyric 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 GABAA 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 (Ki, 90-450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABAA-αβγreceptors but somewhat lower potency as partial agonists at the GABAA-ρ1 receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABAA-αβγreceptors but not the GABAA-ρ1 receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.

AB - Given the heterogeneity within the γ-aminobutyric 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 GABAA 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 (Ki, 90-450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABAA-αβγreceptors but somewhat lower potency as partial agonists at the GABAA-ρ1 receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABAA-αβγreceptors but not the GABAA-ρ1 receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.

U2 - 10.1021/acs.jmedchem.9b00026

DO - 10.1021/acs.jmedchem.9b00026

M3 - Journal article

C2 - 31117514

SN - 0022-2623

VL - 62

SP - 5797

EP - 5809

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 12

ER -

Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

Abstract

Access to Document

Fingerprint

Cite this