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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 greater than 3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexyl-amino)-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.

3-(1,2,5,6-Tetrahydro-4-pyridyl)-5-n-propoxyindole (CP-96,501) was found to be more selective ligand at the serotonin 5-HT1B receptor than the commonly used 5-HT1B agonist, 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-methoxyindole (RU 24969). In rat brain membranes, the tritiated derivative, [3H]CP-96,501, was found to bind with a high affinity (KD, 0.21 nM) to a single binding site (nH, 1.0). The receptor density of this site (Bmax, 72 fmol/mg of protein) matched that of the 5-HT1B receptor determined with [3H]5-HT. Competition curves of 16 serotonergic compounds in [3H]CP-96,501 binding also indicated a single binding site. The rank order of their binding affinities with this new radioligand showed a high degree of correlation with their affinities at the 5-HT1B receptor determined with [3H]5-HT or [125I]iodocyanopindolol. Serotonergic compounds displayed competitive inhibition of [3H]CP-96,501 binding. In the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p], [3H]CP-96,501 to displace [125I]iodocyanopindolol binding was also decreased. These findings are consistent with the agonist nature of CP-96,501. The results of this study suggest that [3H]CP-96,501 is a useful agonist radioligand for the 5-HT1B receptor.

The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of depression has long been suspected and has given impetus to the development of newer compounds that accentuate inhibition of serotonin reuptake. This paper presents structure-activity relationships for a series of cis-1-amino-4-(substituted-aryl)tetralins, which are surprisingly potent and selective inhibitors of serotonin uptake in in vitro models. These compounds are pharmacologically distinct from corresponding members of the trans series, which also potently block uptake of dopamine and norepinephrine. The activity in both cis and trans series is stereospecific, being restricted to the cis-(1S,4S) and the trans-(1R,4S) enantiomers.

The preparation and testing of the two racemic diastereoisomers and the four optically active enantiomers of the title compound in in vitro and in vivo models for determining potential antipsychotic activity are described. Both racemic diastereoisomers and two of the four chiral enantiomers are potent and long-acting neuroleptic compounds.