Steven A. Buckner

Synthesis and pharmacological characterization of ABT-200: a putative novel antidepressant combining potent α-2 antagonism with moderate NE uptake inhibition

Abstract ABT-200, (±)-(1′R*, 3R*)-3-phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylenedioxy-1′-naphthalenyl)methyl]pyrrolidine, ( 1a/b ) represents the first example of a new structural class of potent α-2 antagonists which possess the additional property of norepinephrine (NE) uptake inhibition. This profile of combined activities is expected to have utility in the treatment of depression.

Adrenergic and dopaminergic properties of dopamine sulfoconjugates.

Summary: 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 α1, α2, β1, β2 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 (a) through their metabolic transformation or (b) through displacement of endogenous neurotransmitter.

A new nasal decongestant, A-57219: a comparison with oxymetazoline

2‐(4‐Amino‐3,5‐dichlorobenzyl)imidazolin hydrochloride (A‐57219), has α1‐agonist/α2‐antagonist activity and was more effective and long‐acting than oxymetazoline on canine nasal mucosa, in‐vitro and in‐vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1ṁ65 μg, atomized from a 1 μg mL‐1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.

Synthesis and In Vitro evaluation of fused ring heterocyle-containing angiotensin II antagonists.

Abstract Fused ring heterocyclic analogs of A-81080 (pA2= 9.9) were synthesized and their activities in the rabbit aorta in vitro assay were measued. The best compounds (pA2 = 8.6) in series 1 had R1 = Et, R2 = H, W = X = Z = C-H, and Y = C-OMe or C-COOH. In series 2, the best compound (pA2 = 8.3) had R1 = Et, R2 = H, W = N-Me, X = C-H, and Y = N.

5-Membered ring heterocyclic carboxylic acids as angiotensin II antagonists

A series of 5-membered ring heterocyclic analogs of A-81988 were synthesized in order to determine their activity as angiotensin II antagonists. The activity of these compounds in a rabbit aorta in vitro assay ranged from pA2 values of <6 to 9.3, with the thiazole, thiadiazole and triazole heterocycles being more potent A-II antagonists than the imidazole and pyrazole derivatives. The best activity was seen with the triazole 9b which had a pA2 of 9.3.

Novel adrenergic compounds. I. Receptor interactions of ABBOTT-54741 [(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthtyl)imidazoline], an alpha-adrenergic agonist.

Summary: ABBOTT-54741 was identified as a full α-adrenergic agonist; its interaction with the β-adrenergic receptor was compared to that of norepinephrine. ABBOTT-54741 lacks affinity for α1-adrenergic receptors. In radioligand binding studies, the affinity of ABBOTT-54741 for α-adrenoceptors (as measured against 3H-pra-zosin binding) was K1, – 401 nM, and that for norepinephrine was 388 nM. The affinity of ABBOTT-54741 for α2-adrenoceptors (as measured against 3H-rauwolscine binding) was greater than that of norepinephrine (KIA −7 nM; K1,NE= 37 nM). In vitro. ABBOTT-54741 exhibits high potency in vascular preparations (ED50NE./KIA in rabbit aorta – 12.9; in phenoxyhen/amine-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.e.v.. and nasal), ABBOTT-54741 exhibits cardiovascular effects reflecting the stimulation of both α1- and α2 adrenoceptors consistently with much greater potency than norepinephrine or any other α agonist known to the authors.