Tetrahydrobenzothiophenone Derivatives as a Novel Class of Adenosine Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 39; no. 2; pp. 398 - 406
• Main Authors: van Rhee, A. Michiel, Siddiqi, Suhaib M, Melman, Neli, Shi, Dan, Padgett, William L, Daly, John W, Jacobson, Kenneth A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.01.1996; Amer Chemical Soc
• Subjects: Animals; Binding Sites; Biological and medical sciences; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Miscellaneous; Models, Molecular; Motor Activity - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Purinergic P1 Receptor Antagonists; Rats; Science & Technology; Structure-Activity Relationship; Thiophenes - chemistry; Thiophenes - metabolism; Thiophenes - pharmacology; CELLS; ADENOSINE-A1-RECEPTOR; RAT-BRAIN; ADENYLATE-CYCLASE; BINDING; Rat; Enzyme; Psychotropic; Rodentia; Central nervous system; Phosphorus-oxygen lyases; A1 Adenosine receptor; Lyases; Ketone; In vitro; Modeling; A2 Adenosine receptor; Adenylate cyclase; Vertebrata; Sulfur heterocycle; Mammalia; Structure activity relation; Animal; Molecular model; Van der Waals interaction; Antagonist; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9504823

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 ), which antagonized adenosine agonist-induced inhibition of adenylyl cyclase in rat adipocyte membranes with a K B value of 1.62 ± 0.73 μM and adenosine agonist-induced stimulation of adenylyl cyclase in pheochromocytoma cell membranes with a K B value of 9.19 ± 0.98 μM. 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 vs 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.