Azabicyclic indole esters as potent 5-HT4 receptor antagonists.

The synthesis of a series of azabicyclic indole esters is described and their potency reported as 5-HT4 receptor antagonists. Optimization of the most potent compound (19) by preparing the corresponding oxazino[3,2-a]indole ester afforded 34, which had a pIC50 of 9.5 in the guinea pig distal colon longitudinal muscle myenteric plexus preparation.

[1]  H. Kato,et al.  Studies on antispasmodics. I. Synthesis and anticholinergic activity of 1-, 2-, and 3-diarylmethylenequinolizidine quaternary ammonium salts. , 1979, Chemical and pharmaceutical bulletin.

[2]  I. Murakoshi Studies on the Syntheses of Cyclic Nitrogenous Compounds from Amino Acids. (VII): Syntheses of 3-Substituted Indolizidine and Pyrrolizidine Derivatives from dl -3-(2-Piperidyl) propionic Acid and dl -3-(2-Pyrrolidinyl) propionic Acid@@@ dl -3-(2-Piperidyl) propionic Acid及び dl -3-(2-Pyrrolidinyl) pro , 1958 .

[3]  C. Rader,et al.  Azabicyclic Alcohols. II. Chemical and Catalytic Reduction of the Ketoquinolizidines1 , 1964 .

[4]  J. Sam,et al.  Epimeric 5-hydroxy-5-phenyl-1-azabicyclo [5.4.0] undecanes. , 1976, Journal of pharmaceutical sciences.

[5]  A. Leusen,et al.  A synthetic method for direct conversion of ketones into cyanides. Introduction of a one carbon unit. , 1973 .

[6]  J. Bockaert,et al.  A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. , 1988, Molecular pharmacology.

[7]  N. Morgan,et al.  Antagonism of the stimulatory effects of efaroxan and glibenclamide in rat pancreatic islets by the imidazoline, RX801080 , 1993, British journal of pharmacology.

[8]  H. Kato,et al.  Studies on antispasmodics. V. Synthesis and anticholinergic activity of N-alkyl 1- and 2-diarylmethylene-indolizidinium bromides. , 1980, Chemical & pharmaceutical bulletin.

[9]  C. Rader,et al.  Azabicyclic Alcohols. IV. Stereochemistry of the 1- and 2-Hydroxyindolizidine and Hydroxypyrrolizidine Systems1a , 1966 .

[10]  C. Rader,et al.  Azabicyclic Alcohols. I. Stereochemistry of the Hydroxyquinolizidines1 , 1964 .

[11]  H. Vapaatalo,et al.  Endothelium‐dependent and ‐independent effects of exogenous ATP, adenosine, GTP and guanosine on vascular tone and cyclic nucleotide accumulation of rat mesenteric artery , 1992, British journal of pharmacology.

[12]  J. Mcgiff,et al.  Chloride anion concentration as a determinant of renal vascular responsiveness to vasoconstrictor agents , 1993, British journal of pharmacology.

[13]  J. Fozard,et al.  The 5-HT4 receptor: a place in the sun. , 1992, Trends in pharmacological sciences.