Cholinergic agents structurally related to furtrethonium. 2. Synthesis and antimuscarinic activity of a series of N-[5-[(1'-substituted-acetoxy) methyl]-2-furfuryl]dialkylamines.
In the first part of this study, devoted to the discovery of selective antimuscarinic agents, (+/-)- N-[5-[(1'-phenyl-1'-cyclohexylacetoxy)methyl]-2-furfuryl]dimeth yla mine (5a) proved to be at least 20 times more potent in the rat ileum and bladder than in guinea pig atria. Several (+/-)-N- [5-[(1'-substituted-acetoxy)methyl]-2-furfuryl]dialkylamine analogs of 5a were subsequently prepared. This involved exploration of the tertiary nitrogen substituents and modulation of the lipophilic side chain at position 5 of the furan ring, using the Hansch approach. A QSAR study was conducted to correlate activity with physicochemical properties of substituents. The possibility of describing all compounds in a single model indicates that variations of nitrogen and the lipophilic side chain contribute independently to activity. Compounds 5b, c,j, with bulky lipophilic substituents at the tertiary nitrogen, showed unprecedented selectivity between the two smooth muscle tissues, their antimuscarinic potency being from 10 to 90 times higher in the ileum than in the bladder. It is suggested that their interesting tissue selectivity is probably related to nonspecific phenomena involving the receptor environment, rather than real differences between the muscarinic receptors in the two tissues.
Feriani
A
A
Laboratori Richerche Glaxo, Verona, Italy.
Gaviraghi
G
G
Toson
G
G
Mor
M
M
Barbieri
A
A
Grana
E
E
Boselli
C
C
Guarneri
M
M
Simoni
D
D
Manfredini
S
S
D000818:Animals; D016275:Atrial Function; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009584:Nitrogen / Q000737:chemistry; D009928:Organ Specificity; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
C090927:1-(5-((1'-phenyl-1'-cyclohexylacetoxy)methyl)-2-furfuryl)piperidine; D003509:Cyclohexanecarboxylic Acids; D005663:Furans; D018727:Muscarinic Antagonists; C090928:N-(5-((1'-phenyl-1'-cyclohexylacetoxy)methyl)-2-furfuryl)pentanamine; C090926:N-methyl-N-(5-((1'-phenyl-1'-cyclohexylacetoxy)methyl)-2-furfuryl)cyclohexylamine; D000644:Quaternary Ammonium Compounds; C028530:furtrethonium; D009584:Nitrogen