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.

Adrenergic and dopaminergic properties of dopamine sulfoconjugates.

UNLABELLED: The 3- and 4-sulfate esters of dopamine (DA-3-SO4 and DA-4-SO4, respectively), the two main metabolites of DA, were evaluated for potential intrinsic or indirect catecholaminergic activities. Both compounds lacked any appreciable affinities for alpha 1, alpha 2, beta 1, beta 2 and DA-2 receptors. In the superfused [3H]norepinephrine-preloaded dog saphenous vein, both dopamine sulfates were devoid of any intrinsic inhibitory activity such as observed with dopamine pre- and postsynaptically. In addition, they did not displace the labeled vesicular neurotransmitter as did dopamine. In anesthetized dogs the two compounds failed to stimulate either the dopaminergic receptors (DA-1) of mesenteric vascular beds or the adrenergic receptors mediating the vasodilatory and pressor responses to dopamine. CONCLUSION: In our experimental conditions DA-3-SO4 and DA-4-SO4, the products of dopamine sulfoconjugation, lacked any demonstrable intrinsic affinity and/or efficacy on the dopaminergic and adrenergic receptors directly or indirectly through their metabolic transformation or through displacement of endogenous neurotransmitter.

Modification of the 5' position of purine nucleosides. 2. Synthesis and some cardiovascular properties of adenosine-5'-(N-substituted)carboxamides.

We have shown previously that the esters of adenosine-5'-carboxylic acid (10) represent a new class of potent nontoxic coronary vasodilators. For example, the ethyl ester (12), which is active by an intraduodenal or intravenous route in dogs, causes a large increase in coronary sinus PO2 and coronary blood flow. Because of the pronounced vasoactive properties of the esters of adenosine-5'-carboxylic acid, a systematic study of the corresponding amides (14--50) was undertaken. In addition, several other analogues containing the N1-oxide function (51--52) or 2',3' substituents (3--9, 53--54) were studied.

Modification of the 5' position of purine nucleosides. 1. Synthesis and biological properties of alkyladenosine-5'-carboxylates.

A series of esters of adenosine-5'-carboxylic acid has been prepared. Most of the compounds were nontoxic, causing prolonged increases in coronary sinus PO2 when administered to anesthetized dogs; the ethyl ester was most active. Nitrosation and oxidation of the ethyl ester 12 gave respectively inactive inosine ethyl ester 30 and the fairly active N1-oxide ethyl ester 29.