Synthesis and beta-adrenergic properties of (Z)-N-[3-(alkylamino)-2-hydroxypropylidene](aryl-methyloxy)amines: effects of the configuration around the methyloxyiminomethyl (MOIM) double bond on the biopharmacological properties of MOIM-type beta-blocking agents.
The N-isopropyl- (3a-g) and N-tert-butyl-substituted (4a-g) (Z)-N-(3-(amino)-2-hydroxypropylidene)-(arylmethyloxy)amines were synthesized in order to compare their beta 1- and beta 2-adrenergic properties with those of their previously studied corresponding analogues with the E configuration (1a-g and 2a-g). Compounds 3 and 4 were tested for their affinity for beta 1-a and beta 2-adrenoceptors by radioligand binding experiments, and the compounds with the highest affinity were also assayed for their activity towards the same types of beta-adrenoceptors by functional tests on isolated preparations. The Z-methyloxyiminomethyl (Z-MOIM) compounds 3 and 4 proved to possess, on the whole, affinity (Ki) and activity (PIC50) indices similar to those of the E isomers 1 and 2, thus indicating that for the MOIM-type beta-adrenergic antagonists 1-4, the type of configuration around the MOIM double bond does not have any appreciable effect either on the affinity or on the activity towards beta-adrenoceptors. These results are rationalized on the basis of the steric and electronic analogies existing between the MOIM groups of 1-4 in the two types of configurations (E and Z).
Balsamo
A
A
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Italy.
Breschi
M C
MC
Chiellini
G
G
Lapucci
A
A
Lazzeri
N
N
Macchia
M
M
Martinelli
A
A
Micali
E
E
Nencetti
S
S
Rossello
A
A
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002417:Cattle; D015195:Drug Design; D006168:Guinea Pigs; D007082:Ileum; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014132:Trachea
D000319:Adrenergic beta-Antagonists; D000588:Amines; D007202:Indicators and Reagents; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2