Diphenidol-related diamines as novel muscarinic M4 receptor antagonists.
A series of hydrochloride derivatives 2a-9a and quaternary ammonium derivatives 3b-9b of diphenidol have been synthesized and characterized in receptor binding and cellular functional assays versus human muscarinic M(1)-M(5) receptors expressed in CHO cells. Compound 8b, a methiodide derivative with a bipiperidinyl moiety and a second diphenidol framework, showed a potent and selective M(4) activity as competitive antagonist. Moreover 8b, acting as an allosteric modulator, was able to retard the dissociation rate of [(3)H]-N-methylscopolamine from CHO-M(4) cell membranes exposed to atropine. Taken together, these data suggest that 8b might open new avenues to the discovery of novel multivalent antagonists for the muscarinic receptors.
Varoli
Lucilla
L
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy. lucilla.varoli@unibo.it
Andreani
Aldo
A
Burnelli
Silvia
S
Granaiola
Massimiliano
M
Leoni
Alberto
A
Locatelli
Alessandra
A
Morigi
Rita
R
Rambaldi
Mirella
M
Bedini
Andrea
A
Fazio
Nicola
N
Spampinato
Santi
S
D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003959:Diamines / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D019832:N-Methylscopolamine / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D043588:Receptor, Muscarinic M4 / Q000037:antagonists & inhibitors*; D013194:Staining and Labeling; D013329:Structure-Activity Relationship
D003959:Diamines; D018727:Muscarinic Antagonists; D010880:Piperidines; D043588:Receptor, Muscarinic M4; C004858:diphenidol; D019832:N-Methylscopolamine