Novel and Selective Partial Agonists of 5-HT3 Receptors. 2. Synthesis and Biological Evaluation of Piperazinopyridopyrrolopyrazines, Piperazinopyrroloquinoxalines, and Piperazinopyridopyrroloquinoxalines

• Published in: Journal of medicinal chemistry 1997-06, Vol.40 (12), p.1808-1819
• Main Authors: Prunier, Hervé, Rault, Sylvain, Lancelot, Jean-Charles, Robba, Max, Renard, Pierre, Delagrange, Philippe, Pfeiffer, Bruno, Caignard, Daniel-Henri, Misslin, René, Hamon, Michel
• Format: Article
• Language: English
• Subjects: Animals; Anti-Anxiety Agents - chemical synthesis; Anti-Anxiety Agents - metabolism; Anti-Anxiety Agents - therapeutic use; Anxiety - drug therapy; Anxiety - etiology; Biological and medical sciences; Cattle; Cell Membrane - metabolism; Corpus Striatum - metabolism; Darkness; Frontal Lobe - metabolism; Guanidine; Guanidines - metabolism; Hippocampus - metabolism; Light; Male; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Pyrazines - chemical synthesis; Pyrazines - metabolism; Pyrazines - therapeutic use; Pyridines - chemical synthesis; Pyridines - metabolism; Pyridines - therapeutic use; Rats; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT3; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - metabolism; Serotonin Receptor Agonists - therapeutic use; Serotoninergic system; Structure-Activity Relationship; Swine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960501o

In continuation of our previous work on piperazinopyrrolothienopyrazine derivatives, three series of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifications performed within these new series led to structure−activity relationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 receptors with a selectivity higher than 106. Four of the high-affinity 5-HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrrolopyrazine and the pyrroloquinoxaline series and were characterized in vitro and in vivo as agonists or partial agonists. Compound 8a was also evaluated in the light/dark test where it showed potential anxiolytic-like activity at very low doses per os.