Design, synthesis and binding at cloned muscarinic receptors of N-[5-(1'-substituted-acetoxymethyl)-3-oxadiazolyl] and N-[4-(1'-substituted-acetoxymethyl)-2-dioxolanyl] dialkyl amines.
Few muscarinic antagonists differentiate between the M4 and M2 muscarinic receptors. In a structure activity study, aimed at discovering leads for the development of a M4 muscarinic receptor-selective antagonist, we have synthesized and tested at cloned muscarinic receptors the binding of a group of dioxolane- or oxadiazole-dialkyl amines, and compared them to our compound 1, which contains the furan nucleus. Although none of these agents were particularly potent at M4 receptors (Kd values were typically 30-70 nM), furan derivatives (-)1 and (+)1 were significantly more potent at M4 receptors than at M2 receptors (approximately 3- and 4-fold, respectively). The dioxolane derivatives 12b and 12c were more than 10-fold selective for the M4 versus the M2 receptors, while the dioxolane derivative 12e was 15-fold more potent at M4 receptors than for M2 receptors. However, these agents bound to M3 receptors with potencies like that for the M4 receptor, so they are not M4-selective. The M4/M2 relative selectivities of some of our compounds are similar to the better hexahydrosiladifenidol derivatives, and may provide some important structural clues for the development of potent and selective M4 antagonists.
Manfredini
S
S
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Lampronti
I
I
Vertuani
S
S
Solaroli
N
N
Recanatini
M
M
Bryan
D
D
McKinney
M
M
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000378:metabolism*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000145:classification / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
D000588:Amines; D004148:Dioxolanes; D018727:Muscarinic Antagonists; D010069:Oxadiazoles; D011976:Receptors, Muscarinic