BIOMAT Database Logo BIOMAT Database Logo

Tetrahydrobenzothiophenone derivatives as a novel class of adenosine receptor antagonists. 1996

A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Molecular Recognition Section, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.

A novel class of non-nitrogen-containing heterocycles, the tetrahydrobenzothiophenones, was found to bind to adenosine receptors as antagonists in the micromolar range. Affinity was determined in radioligand-binding assays at rat brain A1 and A2a receptors. A structure-activity analysis indicated that a 3-thioether group is favored and affinity at A2a, but not at A1, receptors is highly dependent on this thioether substituent. A carboxylic acid-derived substituent is required at the 1-position of the thiophene ring, with esters being more potent in binding at A1 receptors than the corresponding carboxyl hydrazide or carboxylic acid derivatives. The methyl (15) and ethyl (16) esters are about equipotent at A1 but not at A2a receptors. A 4-keto group on the saturated ring is favored for receptor affinity. Dimethyl substitution at the 6-position of the saturated ring is allowed. One of the most potent derivatives was the nonselective compound ethyl 3-(benzylthio)-4-oxo-4,5,6,7-tetrahydrobenzo[c] thiophene-1-carboxylate (BTH4, 7; Figure 1), which antagonized adenosine agonist-induced inhibition of adenylyl cyclase in rat adipocyte membranes with a KB value of 1.62 +/- 0.73 microM and adenosine agonist-induced stimulation of adenylyl cyclase in pheochromocytoma cell membranes with a KB value of 9.19 +/- 0.98 microM. Displacement of radioligand binding by BTH4 (7) at cloned human A3 receptors was negligible but one slightly A3 selective compound (11, 3.9-fold over A1 and >7.5-fold over A2a) was found. A 1-methylpropyl thioether (17) was 29-fold selective for A1 and A2a receptors. BTH4 (7) alone, at 10 mg/kg, stimulated locomotor activity in mice but paradoxically acted, under certain circumstances, synergistically with an A1 selective agonist to depress locomotor activity. A pharmacophore model relating structural features of xanthine and non-xanthine adenosine antagonists to BTH4 (7) suggests a high degree of similarity in electrostatic surfaces, assuming that the thiophene ring superimposes the region of the uracil ring of xanthines.

UI MeSH Term Description Entries
D008297 Male Males
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D009043 Motor Activity Body movements of a human or an animal as a behavioral phenomenon. Activities, Motor,Activity, Motor,Motor Activities
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013876 Thiophenes A monocyclic heteroarene furan in which the oxygen atom is replaced by a sulfur. Thiophene
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus

Related Publications

A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Xanthine derivatives as adenosine receptor antagonists.
July 1982, European journal of pharmacology,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Thiazole and thiadiazole analogues as a novel class of adenosine receptor antagonists.
March 2001, Journal of medicinal chemistry,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
1,5-Benzodioxepin derivatives as a novel class of muscarinic M3 receptor antagonists.
February 2007, Bioorganic & medicinal chemistry letters,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Benzothiazinones: a novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives.
April 2012, Journal of medicinal chemistry,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Synthesis of alkyne derivatives of a novel triazolopyrazine as A(2A) adenosine receptor antagonists.
February 2005, Bioorganic & medicinal chemistry letters,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A(3) adenosine receptor antagonists.
August 2002, Journal of medicinal chemistry,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
N-Methylbenzanilide derivatives as a novel class of selective V(1A) receptor antagonists.
January 2002, Bioorganic & medicinal chemistry letters,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists.
January 2015, Future medicinal chemistry,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Pyrazolo-triazolo-pyrimidine derivatives as adenosine receptor antagonists: a possible template for adenosine receptor subtypes?
January 2002, Current pharmaceutical design,
A M van Rhee, and S M Siddiqi, and N Melman, and D Shi, and W L Padgett, and J W Daly, and K A Jacobson
Discovery of aminoquinazoline derivatives as human A(2A) adenosine receptor antagonists.
February 2016, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!