Synthesis and pharmacological activity of fluorescent histamine H1 receptor antagonists related to mepyramine

• Published in: Bioorganic & medicinal chemistry letters 2003-04, Vol.13 (7), p.1245-1248
• Main Authors: LIANTAO LI, KRACHT, Julia, SHIQI PENG, BERNHARDT, Günther, BUSCHAUER, Armin
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain Neoplasms - metabolism; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - pharmacology; Fura-2 - analogs & derivatives; Fura-2 - chemistry; Glioblastoma - metabolism; Guinea Pigs; Histamine H1 Antagonists - chemical synthesis; Histamine H1 Antagonists - pharmacology; Humans; Ileum - drug effects; Ileum - metabolism; In Vitro Techniques; Indicators and Reagents; Medical sciences; Miscellaneous; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Pyrilamine - analogs & derivatives; Pyrilamine - chemical synthesis; Pyrilamine - pharmacology; Spectrophotometry, Ultraviolet; Tumor Cells, Cultured
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/s0960-894x(03)00113-6

Fluorescently labeled histamine H(1) receptor antagonists were synthesized starting from N-demethylmepyramine by introduction of omega-aminoalkyl chains (2-8 methylene groups in length) followed by derivatization of the terminal NH(2) group with various fluorophores (fluorescein, naphthofluorescein, rhodamine, tetramethylrhodamine, BODIPY, dansyl, and nitrobenzoxadiazole (NBD)). On the isolated guinea pig ileum and in a Ca(2+) assay on U373MG human glioblastoma cells the highest H(1) antagonistic activities were found in 5- and 6-carboxyfluorescein labeled compounds with hexa- and octamethylene spacers and in an analogous NBD-aminohexanoyl derivative (pA(2) or pK(B) values in the range: 8.3-9.0; compared to 9.3-9.4 for mepyramine).