Pharmacological differentiation of pre- and post-junctional alpha 2-adrenoceptors.

It is now recognized that two post-junctional alpha-adrenoceptors mediate vascular constriction. The vascular alpha 2-adrenoceptors seem to be particularly sensitive to circulating catecholamine levels, in contrast to the alpha 1-adrenoceptors, which are activated primarily by neuronally released norepinephrine. Most alpha 2-adrenoceptor antagonists do not discriminate between the pre-junctional neuroinhibitory alpha 2-adrenoceptor and the post-junctional vascular alpha 2-adrenoceptor. However, we have synthesized and characterized a compound (SK&F 104078: 6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine) which is a potent antagonist at post-junctional vascular alpha 2-adrenoceptors in vitro but has no effect at pre-junctional neuroinhibitory alpha 2-adrenoceptors. The post-junctional selectivity of SK&F 104078 has been confirmed by in vivo studies determining pre- and post-junctional alpha 2-adrenoceptor antagonist activity in the pithed rat. The ability to selectively block post-junctional alpha 2-adrenoceptors offers a novel approach to antihypertensive therapy, since the vasoconstrictor effects of circulating catecholamines can be attenuated without influencing the feedback control of transmitter release operating via pre-junctional alpha 2-adrenoceptors, and excess sympathoadrenal tone can be reduced without affecting normal neurovascular transmission.

4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: a prejunctional dopamine receptor agonist.

4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone (1c) (SK&F 101468) is a potent and selective prejunctional dopamine receptor agonist. It caused a dose-related inhibition of the constrictor response to electrical stimulation in the isolated perfused rabbit ear artery (EC50 = 100 nM), and this response was antagonized by (S)-sulpiride (KB = 7 nM). Compound 1c did not stimulate or block dopamine-sensitive adenylate cyclase and did not produce stimulation of the central nervous system in rats. It was prepared from (2-methyl-3-nitrophenyl)acetic acid in a multistep sequence based on the Reissert indole synthesis.

Gastric antisecretory 9H-xanthen-9-amines.

A series of 9H-xanthen-9-amines possessing a wide variety of nitrogen substituents at C-9 was prepared for evaluation of gastric antisecretory activity. These substituents included the acetamidine, imidate, pyrimidine, thiazoline, quinuclidine, 2-hydrazinopyridine, aminopiperidine, aminoalkylimidazole, and aminoalkylpyridine moieties. The majority of compounds in this series inhibited gastric acid secretion when tested orally in the pylorus-ligated rat. Potency was increased by intraduodenal administration and diminished by incubation with gastric juice, suggesting partial degradation of the compounds in the gastric environment. A representative example, 3-(9H-xanthen-9-ylamino)-1-ethylpiperidine, exhibited similar activity in dogs, although no free compound could be detected in the blood. It is therefore hypothesized that this compound is either rapidly bound to tissue and/or metabolized to an active species.

Imidodisulfamides. 2. Substituted 1,2,3,4-tetrahydroisoquinolinylsulfonic imides as antagonists of slow-reacting substance of anaphylaxis.

As part of a study of the influence of structural modifications of N',N'-bis(aralkyl)imidodisulfamides on their ability to selectively antagonize SRS-A activity, a few conformationally constrained structures were examined. Among these derivatives having a conformationally restricted alkylene side chain, substituted 1,2,3,4-tetrahydroisoquinolinylsulfonic imides produced optimum SRS-A antagonist activity and selectivity. These compounds were tested for antagonism of partially purified SRS-A induced contractions of isolated guinea pig ileum. In this series of tetrahydroisoquinolines, the effect of aromatic ring substitution, as well as substitution and variation of the size of the heterocyclic ring on SRS-A antagonist activity and selectivity, was studied.

Imidodisulfamides. 1. A novel class of antagonists of slow-reacting substance of anaphylaxis.

A series of N',N"-bis(aryl)- and N',N"-(aralkyl)imidodisulfamides was prepared and evaluated as antagonists of slow-reacting substance of anaphylaxis (SRS-A) induced contractions of isolated guinea pig ileum. Some of these compounds, notably N',N"-bis(4-phenylbutyl)-, N',N"-bis[2-(4-chlorophenyl)ethyl]-, and N',N"-bis[2-(4-bromophenyl)ethyl]imidodisulfamides (16, 22, and 26), were moderately potent and selective antagonists of SRS-A. The influence of lipophilic (pi) and electronic (sigma) factors on SRS-A antagonist activity appears to be of considerable importance to the derivation of potent and selective SRS-A antagonists.