beta 1-selective adrenoceptor antagonists. 1. Synthesis and beta-adrenergic blocking activity of a series of binary (aryloxy)propanolamines.

A series of binary (aryloxy)propanolamines has been prepared and examined in vitro and in vivo for beta-adrenoreceptor blocking activity. These symmetrical compounds consist of two (S)-(phenyloxy)propanolamine pharmacophores coupled through alkylenedioxy or poly(oxyethylenedioxy) linking units of varying lengths. Examples of such binary compounds linked through the 2,2', 3,3', and 4,4' positions in the aromatic rings of the pharmacophores have been prepared. In vitro and in vivo test data indicate that the 2,2' compounds tend to be selective beta 2-adrenergic blocking agents, the 4,4' binaries tend to be selective beta 1-blocking agents, and those compounds with 3,3' linkages exhibit intermediate selectivities. One of the 4,4'-linked binary compounds, 4s, exhibited potent, cardioselective beta-blockade in vivo, which was of short duration and was accompanied by a prolonged tachycardia.

beta 1-selective adrenoceptor antagonists. 2. 4-ether-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines was prepared and examined for beta-adrenoceptor activity. Some of the compounds, especially the [4-[2-[[2-(4-fluorophenyl)ethyl] oxy]ethoxy]phenoxy]propanolamines (14, 15, and 24), showed potent beta 1-blockade with virtually no beta 2-blockade at doses over a 1000 times greater. The compounds also possessed partial agonist activity. Structure-activity relationships are discussed, and conclusions are drawn about the binding sites on beta-adrenoceptors.

Beta 1-selective adrenoceptor antagonists. 3. 4-Azolyl-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines has been prepared and examined for beta-adrenoceptor activity. The 4-substituents, di- and triazole ring systems connected to the phenoxy ring by different length chains, were chosen as a means of introducing cardioselectivity. This has been achieved, especially in the 1-[4-[(4-chloropyrazol-1-yl)methoxy] phenoxy]-3-(isopropylamino)-2-propanol (11), the 4-[(2H-1,2,3-triazol-2-yl)methoxy] analogue (21), and the 4-[2-(2H-1,2,3-triazol-2-yl)ethoxy] analogue (22), which show potent beta 1-blockade with selectivity ratios in excess of 100:1. Structure-activity relationships are discussed, and the optimum position of the heteroatom in the 4-substituent is defined.

The prejunctional actions of some non-depolarizing blocking drugs.

1. Trains of end-plate potentials (e.p.p.s) have been recorded from the isolated tenuissimus of the cat. The muscle was paralyzed either by transversely cutting the muscle fibres or by non-depolarizing blocking drugs.2. The following parameters of transmitter synthesis, storage and release have been calculated: the quantal content of the first e.p.p. in the train, the size of the available store, fractional release, quantum size, and the rate of refilling of the available store.3. Tubocurarine and benzoquinonium depressed the rate of refilling of the available store causing its depletion at high rates of stimulation. This was offset by an increase in fractional release, which in the case of tubocurarine was sufficient for the quantal content of the first e.p.p. to be unchanged.4. Dimethyltubocurarine and pancuronium had a similar effect to tubocurarine on the rate of refilling of the store and depletion of the store at high rates of stimulation but did not increase fractional release. There was, therefore, a decrease in the quantal content of the first e.p.p.5. Lignocaine depressed the rate of refilling of the store and depleted the store at high rates of stimulation. Fractional release was also depressed.6. It is suggested that the non-depolarizing drugs have a weak local anaesthetic action retarding the influx of sodium into the nerve terminal which slows the rate of refilling of the store. This effect is due to the quaternary ammonium head. The presence of a phenolic group increases fractional release due either to an increased influx of calcium into the nerve terminal or to a potentiation of the actions of calcium.

The mechanism of the facilitatory action of edrophonium in cat skeletal muscle.

1. The effects of edrophonium have been observed in the transversely cut tenuissimus muscle of the cat.2. Concentrations of edrophonium 10(-7)M to 10(-5)M increased the amplitude of the end-plate potential (e.p.p.) but produced no greater increase in time course than previously observed in curarized muscle.3. When the e.p.p. and gross nerve action potential were recorded simultaneously, antidromic discharges were observed in the motor nerve concomitantly with repetitive e.p.ps in the presence of edrophonium.4. Edrophonium produced no effect on the input resistance or equilibrium potential of the end-plate.5. The fractional release of transmitter was significantly increased by edrophonium but there was no increase in the quantal release of transmitter in the transversely cut muscle preparation.6. In curarized muscle edrophonium also increased the quantal release, the size of the available store of transmitter and the rate of refilling of the available store.7. It is concluded that edrophonium facilitates transmission to skeletal muscle by inducing a repetitive antidromic discharge in the nerve, following orthodromic stimulation. The antidromic discharge propagates by axon reflex to other nerve terminals of the same motor unit producing repetitive e.p.ps. It is also suggested that edrophonium antagonizes tubocurarine by acting as a partial agonist at the motor nerve terminal.

The response of cat airways to histamine in vivo and in vitro.

The effects of histamine have been examined in anaesthetized cats and on cat cat isolated lung parenchyma strip. Histamine infused intravenously for 2 min produced a small and inconsistent effect on central airways and a small but consistent constriction of peripheral airways. Histamine bronchoconstriction of the central airways was unmasked by non-selective and beta 2-adrenoceptor blockade but not by beta 1-adrenoceptor blockade. This bronchoconstriction was antagonized by atropine but not by cimetidine or prazosin. Bronchoconstriction of the peripheral airways was not affected in a dose-related manner by beta-adrenoceptor blockade. The bronchoconstriction was antagonized by mepyramine but not by atropine or prazosin. beta-Adrenoceptor antagonists produced a bell-shaped dose-response curve on histamine contractions in cat isolated lung parenchyma strip. Strips of lung parenchyma obtained from reserpine-treated cats produced a larger contraction to histamine which was not potentiated by propranolol. It is concluded that in the central airways, histamine bronchoconstriction produced by an action on irritant receptors is masked by an action on beta 2-adrenoceptors of catecholamines released locally and from the adrenal glands. In the peripheral airways, histamine bronchoconstriction is mediated by H1-receptors and beta 2-adrenoceptor blockade may either potentiate or antagonize the histamine response depending on the concentration.

Neuronal muscarinic receptors attenuate vagally-induced contraction of feline bronchial smooth muscle.

In anaesthetized cats, stimulation of the vagus nerves produced bradycardia and a bronchoconstriction which was measured as an increase in lung resistance (RL) and a fall in dynamic lung compliance (Cdyn); these effects were abolished by atropine. Gallamine potentiated vagally-mediated changes in RL and Cdyn at doses that blocked muscarinic receptors in the heart and inhibited neuromuscular transmission. (+)-Tubocurarine and suxamethonium did not affect the response of the lung or the heart to vagal stimulation. Bronchoconstriction induced by intravenous acetylcholine was not potentiated by gallamine, indicating that postsynaptic muscarinic receptors in the lung and changes in muscle tone were not involved. Potentiation of vagally-induced bronchoconstriction appears to be due to blockade of inhibitory muscarinic receptors located in the pulmonary parasympathetic nerves innervating both central and peripheral airways. Pilocarpine was an agonist for these neuronal receptors as it inhibited vagally-induced bronchoconstriction at low doses (10 ng to 1 microgram kg-1). The results demonstrate that gallamine is an antagonist and pilocarpine an agonist at neuronal muscarinic receptors which attenuate parasympathetic nerve activity in feline lung.

The effects of bufuralol, a beta-adrenoceptor antagonist with predominant beta 2-adrenoceptor agonistic activity, in the cat and the dog.

The effects of bufuralol and its carbinol metabolite have been compared with those of propranolol in the anaesthetised and conscious cat and dog. Bufuralol and its carbinol metabolite are nonselective beta-adrenoceptor antagonists; the former has equivalent potency to propranolol, whereas the latter is six times more potent. In anaesthetised animals both bufuralol and its metabolite exhibited partial agonistic activity, resulting in tachycardia and vasodilation. In conscious cats there was no change in heart rate or slight bradycardia, whereas in dogs both compounds again produced tachycardia. In anaesthetised and conscious cats and conscious dogs, both bufuralol and the metabolite increased abdominal aortic blood flow. There was a reduction in blood pressure in the conscious dog. It is concluded that the partial agonistic activity of bufuralol and its carbinol metabolite is exerted mainly at the beta 2-adrenoceptor, producing vasodilation and reducing peripheral resistance, resulting in a reduction in blood pressure with a long duration of action.