Ligand‐Based Design, Synthesis, and Pharmacological Evaluation of 3‐Methoxyquinoxalin‐2‐carboxamides as Structurally Novel Serotonin Type‐3 Receptor Antagonists

Employing a ligand‐based approach, 3‐methoxyquinoxalin‐2‐carboxamides were designed as serotonin type‐3 (5‐HT3) receptor antagonists and synthesized from the starting material o‐phenylenediamine in a sequence of reactions. The structures of the synthesized compounds were confirmed by spectral data. These carboxamides were investigated for their 5‐HT3 receptor antagonisms in longitudinal muscle myenteric plexus preparations from guinea‐pig ileum against a standard 5‐HT3 agonist, 2‐methy‐5‐HT, and their antagonism activities are expressed as pA2 values. Compounds 6a (pA2: 7.2), 6e (pA2: 7.0), 6f (pA2: 7.5), 6g (pA2: 7.5), 6n (pA2: 7.0), and 6o (pA2: 7.2) exhibited antagonism greater than that of the standard 5‐HT3 antagonist, ondansetron (pA2: 6.9).

[1]  D. Pandey,et al.  Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT3) receptor antagonists , 2011, Journal of enzyme inhibition and medicinal chemistry.

[2]  R. Mahesh,et al.  Citric acid: An efficient and green catalyst for rapid one pot synthesis of quinoxaline derivatives at room temperature , 2011 .

[3]  D. Pandey,et al.  Discovery of new anti-depressants from structurally novel 5-HT3 receptor antagonists: design, synthesis and pharmacological evaluation of 3-ethoxyquinoxalin-2-carboxamides. , 2011, Bioorganic & medicinal chemistry letters.

[4]  P. Hesketh.  Chemotherapy-induced nausea and vomiting. , 2008, The New England journal of medicine.

[5]  H. Schmoll,et al.  Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations. , 2007, The oncologist.

[6]  Gernot A. Eller,et al.  Pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinoxalin-4(1H)-one: Synthesis and characterization of a novel tetracyclic ring system , 2007 .

[7]  M. Aapro,et al.  Comparative activity of antiemetic drugs. , 2007, Critical reviews in oncology/hematology.

[8]  R. Mahesh,et al.  Synthesis and biological evaluation of a novel structural type of serotonin 5-HT3 receptor antagonists. , 2006, Bioorganic & medicinal chemistry letters.

[9]  R. Mahesh,et al.  Pharmacophore based synthesis of 3-chloroquinoxaline-2-carboxamides as serotonin3 (5-HT3) receptor antagonist. , 2004, Biological & pharmaceutical bulletin.

[10]  G. Mauceri,et al.  Central nervous system side-effects of 5-HT3-receptor antagonists in elderly cancer patients treated with chemotherapy. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  M. Villar,et al.  Distribution of serotonin in the central nervous system of the blood‐feeding heteropteran, Triatoma infestans (Heteroptera: Reduviidae) , 2004, Journal of morphology.

[12]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[13]  T. Suzuki,et al.  Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. I. Synthesis and structure-activity relationships of conformationally restricted fused imidazole derivatives. , 1996, Chemical & pharmaceutical bulletin.

[14]  P P Humphrey,et al.  International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). , 1994, Pharmacological reviews.

[15]  R M Eglen,et al.  2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists. , 1993, Journal of medicinal chemistry.

[16]  L. Cubeddu,et al.  Mechanisms by which cancer chemotherapeutic drugs induce emesis. , 1992, Seminars in oncology.

[17]  R. Myers,et al.  Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. , 1991, Science.

[18]  R. Hoffmann,et al.  Conformation-activity relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site. , 1990, Journal of medicinal chemistry.

[19]  S B Kaye,et al.  On the receiving end--patient perception of the side-effects of cancer chemotherapy. , 1983, European journal of cancer & clinical oncology.

[20]  D. Mackay.  How should values of pA2 and affinity constants for pharmacological competitive antagonists be estimated? , 1978, The Journal of pharmacy and pharmacology.

[21]  G. Tyce,et al.  Origin and Metabolism of Serotonin , 1990, Journal of cardiovascular pharmacology.

[22]  W. Paton,et al.  The origin of acetylcholine released from guinea‐pig intestine and longitudinal muscle strips , 1968, The Journal of physiology.