Novel adrenergic compounds. I. Receptor interactions of ABBOTT-54741 [(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthtyl)imidazoline], an alpha-adrenergic agonist.
ABBOTT-54741 was identified as a full alpha-adrenergic agonist; its interaction with the alpha-adrenergic receptor was compared to that of norepinephrine. ABBOTT-54741 lacks affinity for beta-adrenergic receptors. In radioligand binding studies, the affinity of ABBOTT-54741 for alpha 1-adrenoceptors (as measured against 3H-prazosin binding) was KI = 401 nM, and that for norepinephrine was 388 nM. The affinity of ABBOTT-54741 for alpha 2-adrenoceptors (as measured against 3H-rauwolscine binding) was greater than that of norepinephrine (KIA = 7 nM; KI NE = 37 nM). In vitro, ABBOTT-54741 exhibits high potency in vascular preparations (ED50NE/ED50A in rabbit aorta = 12.9; in phenoxybenzamine-treated dog saphenous vein = 188.5). In rabbit pulmonary artery, it shows greater potency for the presynaptic than postsynaptic receptors, corroborating the observations of selectivity obtained in binding studies. The observations in vivo reflect that in isolated tissues. In different species (dog, rat) and via different routes of administration (i.v., p.o., i.c.v., and nasal), ABBOTT-54741 exhibits cardiovascular effects reflecting the stimulation of both alpha 1- and alpha 2-adrenoceptors consistently with much greater potency than norepinephrine or any other alpha agonist known to the authors.
Kyncl
J J
JJ
Research and Development Division of Abbott Laboratories, North Chicago, Illinois 60064.
DeBernardis
J F
JF
Bush
E N
EN
Buckner
S A
SA
Brondyk
H
H
D000322:Adrenergic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012501:Saphenous Vein / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*
D000322:Adrenergic Agonists; D007093:Imidazoles; D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; C052396:2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline