The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A(1) adenosine receptor

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Abstract

A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A(1) adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with varying the size of the cycloalkyl ring. 2-Aminothiophenes with amide and hydrazide groups in the 3-position were completely inactive in an A(1)-AR-mediated ERK1/2 phosphorylation assay, yet most of the 3-benzoyl substituted compounds exhibited allosteric effects on responses mediated by the orthosteric agonist, R-PIA. Despite finding an increase in both agonistic and allosteric activities by going from a cyclopentyl ring to a cyclohexyl ring in the 3-benzoyl series, decreases were observed when further increasing the ring size. Varying the substituents on the phenyl ring of the 3-benzoyl group also affected the activity of these compounds.
Original languageEnglish
Pages (from-to)3704 - 3707
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number12
DOIs
Publication statusPublished - 2011

Cite this

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title = "The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A(1) adenosine receptor",
abstract = "A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A(1) adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with varying the size of the cycloalkyl ring. 2-Aminothiophenes with amide and hydrazide groups in the 3-position were completely inactive in an A(1)-AR-mediated ERK1/2 phosphorylation assay, yet most of the 3-benzoyl substituted compounds exhibited allosteric effects on responses mediated by the orthosteric agonist, R-PIA. Despite finding an increase in both agonistic and allosteric activities by going from a cyclopentyl ring to a cyclohexyl ring in the 3-benzoyl series, decreases were observed when further increasing the ring size. Varying the substituents on the phenyl ring of the 3-benzoyl group also affected the activity of these compounds.",
author = "Luigi Aurelio and Arthur Christopoulos and Bernard Flynn and Peter Scammells and Patrick Sexton and Celine Valant",
year = "2011",
doi = "10.1016/j.bmcl.2011.04.080",
language = "English",
volume = "21",
pages = "3704 -- 3707",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Pergamon",
number = "12",

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TY - JOUR

T1 - The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A(1) adenosine receptor

AU - Aurelio, Luigi

AU - Christopoulos, Arthur

AU - Flynn, Bernard

AU - Scammells, Peter

AU - Sexton, Patrick

AU - Valant, Celine

PY - 2011

Y1 - 2011

N2 - A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A(1) adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with varying the size of the cycloalkyl ring. 2-Aminothiophenes with amide and hydrazide groups in the 3-position were completely inactive in an A(1)-AR-mediated ERK1/2 phosphorylation assay, yet most of the 3-benzoyl substituted compounds exhibited allosteric effects on responses mediated by the orthosteric agonist, R-PIA. Despite finding an increase in both agonistic and allosteric activities by going from a cyclopentyl ring to a cyclohexyl ring in the 3-benzoyl series, decreases were observed when further increasing the ring size. Varying the substituents on the phenyl ring of the 3-benzoyl group also affected the activity of these compounds.

AB - A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A(1) adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with varying the size of the cycloalkyl ring. 2-Aminothiophenes with amide and hydrazide groups in the 3-position were completely inactive in an A(1)-AR-mediated ERK1/2 phosphorylation assay, yet most of the 3-benzoyl substituted compounds exhibited allosteric effects on responses mediated by the orthosteric agonist, R-PIA. Despite finding an increase in both agonistic and allosteric activities by going from a cyclopentyl ring to a cyclohexyl ring in the 3-benzoyl series, decreases were observed when further increasing the ring size. Varying the substituents on the phenyl ring of the 3-benzoyl group also affected the activity of these compounds.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21612922

U2 - 10.1016/j.bmcl.2011.04.080

DO - 10.1016/j.bmcl.2011.04.080

M3 - Article

VL - 21

SP - 3704

EP - 3707

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 12

ER -