Design, synthesis, and biological evaluation of pirenzepine analogs bearing a 1,2-cyclohexanediamine and perhydroquinoxaline units in exchange for the piperazine ring as antimuscarinics.
Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
Minarini
Anna
A
Department of Pharmaceutical Sciences, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Marucci
Gabriella
G
Bellucci
Cristina
C
Giorgi
Gianluca
G
Tumiatti
Vincenzo
V
Bolognesi
Maria Laura
ML
Matera
Riccardo
R
Rosini
Michela
M
Melchiorre
Carlo
C
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003514:Cyclohexylamines / Q000737:chemistry*; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011810:Quinoxalines / Q000737:chemistry*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D003514:Cyclohexylamines; D018727:Muscarinic Antagonists; D011810:Quinoxalines; D011976:Receptors, Muscarinic; D010890:Pirenzepine; C030435:1,2-cyclohexanediamine