4-Aminotriazoloquinoxalines. A Novel Class of Potent Adenosine Receptor Antagonists and Potential Rapid-Onset Antidepressants

Article abstract of DOI:10.1021/jm00170a031

A series of 4-amino<1,2,4>triazolo<4,3-a>quinoxalines has been prepared.Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents.Optimal activity in this test is associated with hydrogen, CF3, or small alkyl groups in the 1-position, with NH2, NH-acetyl, or amines substituted with small alkyl groups in the 4-position, and with hydrogen or 8-halogen substituents in the aromatic ring.Furthermore, many of these 4-amino<1,2,4)triazolo<4,3-a>quinoxalines bind avidly, and in some cases very selectively, to adenosine A₁ and A₂ receptors.A₁ affinity of these compounds was measured by their inhibition of tritiated CHA (N⁶-cyclohexyladenosine) binding in rat cerebral cortex membranes and A₂ affinity by their inhibition of tritiated NECA (5'-(N-ethylcarbamoyl)adenosine) binding to rat striatal homogenate in the presence of cold N⁶-cyclopentyladenosine.Structure-activity relationship (SAR) studies show that best A₁ affinity is associated with ethyl, CF3, or C2F5 in the 1-position, NH-ⁱPr or NH-cycloalkyl in the 4-position, and with an 8-chloro substituent.Affinity at the A₂ receptor is mostly dependent on the presence of an NH2 group in the 4-position and is enhanced by phenyl, CF3, or ethyl in the 1-position.The most selective A₁ ligand by a factor of >3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexylamino)-1-(trifluoromethyl)<1,2,4>triazolo<4,3-a>quinoxaline) with an IC50 of 28 nM at the A₁ receptor.The most potent A₂ ligand is 128 (CP-66,713; 4-amino-8-chloro-1-phenyl<1,2,4>triazolo<4,3-a>quinoxaline) with an IC50 of 21 nM at the A₂ receptor and a 13-fold selectivity for this receptor.Representatives from this series appear to act as antagonists at both A₁ and A₂ receptors since they antagonize the inhibiting action of CHA on norepinephrine-stimulated cAMP formation in fat cells and they decrease cAMP accumulation induced by adenosine in limbic forebrain slices.Thus certain members of this 4-amino<1,2,4>triazolo<4,3-a>quinoxaline series are among the most potent and A₁ or A₂ selective non-xanthine adenosine antagonists known.