We investigated the blockade of the positive inotropic effects of 5-hydroxytryptamine (5-HT) by SB 203 186 (piperidinoethyl-indole-3-carboxylate hydrochloride) and its affinity for 5-HT4 receptors of human right atrium and piglet left atrium. We also compared the blocking effects of SB 203 186 against 5-HT-evoked tachycardia in anaesthetised adult Yucatan minipigs as well as new-born Camborough piglets. SB 203 186 caused competitive antagonism of the positive inotropic effects of 5-HT in electrically paced atrial preparations of man (pKB = 8.9) and piglet (pKB = 8.5) at concentrations (up to 0.3 micromol/l) which were devoid of depressant or stimulant effects. The affinity of SB 203 186 for atrial 5-HT4 receptors was 30-160 times higher than that of tropisetron. 5-HT caused tachycardia with similar potency and efficacy in Yucatan minipigs and new-born Camborough piglets. SB 203 186 (0.1-3 mg/kg, i.v.) surmountably antagonised 5-HT-evoked tachycardia in anaesthetised Yucatan minipigs or new-born Camborough piglets with similar potency. The blocking potency of SB 203 186 in Yucatan minipigs was 17 times higher than that of tropisetron. Intraduodenally administered SB 203 186 (0.3-3 mg/kg) to new-born Camborough piglets produced blockade of 5-HT-evoked tachycardia which was maximal after 20 min and lasted for more than 3 h with 0.3 mg/kg. The antagonism produced by the SB 203 186 administration in new-born Camborough piglets was dose-related and threefold greater through the intravenous route than through the intraduodenal route. We conclude that SB 203 186 is an antagonist with nanomolar affinity for both human and porcine atrial 5-HT4 receptor. The in vivo results demonstrate that the sinoatrial 5-HT4 receptors function is similar in new-born Camborough piglets and adult Yucatan minipigs. Both porcine breeds are valid models for human atrial 5-HT4 receptors as demonstrated with the antagonist SB 203 186.

A series of new 6-[4-[[(aryloxy)acyl]amino]phenyl]-4,5-dihydropyridazinones have been synthesized and evaluated as combined vasodilator/beta-adrenoceptor antagonists and potential antihypertensive agents. Many of the early compounds displayed an unacceptably high level of intrinsic sympathomimetic activity (ISA) and a relatively short duration of action. Disubstitution in the 2,3-positions or in the 4-position of the aryloxy ring gave compounds with low ISA levels and, in some instances, improved duration of action. All of the compounds were vasodilators, but the 5-methylpyridazinone derivatives showed consistently greater antihypertensive activity than their 5-H lower homologues. Further detailed pharmacological investigations led to the selection of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (4t) (SK&F 95018) as a development candidate.

1. The properties of a new antihypertensive agent, SK&F 92657, DL-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, have been studied. 2. The compound caused a sustained fall in blood pressure in several species as a result of precapillary vasodilatation, particularly in the renal and coronary vasculatures. 3. The beta-adrenoreceptor-blocking actions of SK&F 92657 prevent reflex cadiac stimulation.

The pharmacological properties of SK&F 94120 on the cardiovascular system have been studied in laboratory animal species. The compound was shown to have positive inotropic activity on hearts from guinea-pig, cat, dog and marmoset in-vitro and in cat and dog in-vivo. These responses in-vivo occurred in association with minimal changes in heart rate. Positive inotropic activity was not caused by SK&F 94120 in rat or hamster hearts in-vitro, thereby indicating a species dependence in myocardial response. SK&F 94120 was shown to have vasodilator activity in cats in-vivo. Detailed studies carried out on anaesthetized cats indicated that the compound caused a balanced dilatation of both resistance and capacitance blood vessels. Haemodynamic studies in anaesthetized cats indicated that, as a consequence of the positive inotropic and vasodilator actions, SK&F 94120 causes significant increases in cardiac output and stroke volume. Studies in conscious dogs showed the compound to be active as a positive inotrope after oral administration. The above properties suggest that this compound possesses useful haemodynamic properties for the treatment of congestive heart failure.

Several known inhibitors of mono-amine oxidase (iproniazid, isocarboxazid, n.alamide, phenelzine, pheniprazine and tranylcypromine) were tested for their ability to (i) inhibit the mono-amine oxidase activity of a rat brain mitochondrial preparation in vitro; (ii) potentiate the action of tryptamine on the isolated rat fundal strip preparation; and (iii) potentiate the acute toxicity of tryptamine in mice. There was some correlation between the order of potency of the drugs in the three tests, particularly in inhibiting the enzyme activity in the Warburg and in the tryptamine toxicity test in mice. Exceptions to this were isocarboxazid which had unexpectedly high activity on the rat fundal strip preparation, and tranylcypromine which was devoid of tryptamine-potentiation action on the rat fundus preparation although it inhibited rat brain mono-amine oxidase in vitro and potentiated the action of tryptamine in vivo. Tranylcypromine was considerably less active in inhibiting the mono-amine oxidase of rat fundus than rat brain tissue in vitro, while iproniazid and isocarboxazid had about the same potency on the enzyme from the two tissues.When investigating the action of various analogues of tryptamine on the isolated rat fundal strip preparation, Vane (1959) observed that the addition to the organ bath of the mono-amine oxidase inhibitor 3-phenylisopropylhydrazine caused a potentiation of the action of tryptamine while having no effect on the contractions due to 5-hydroxytryptamine. This was explained as being due to the penetration of the tryptamine but not 5-hydroxytryptamine inside the cell where it could be inactivated by mono-amine oxidase.In view of the current interest in drugs that effect the metabolism of catechol and indole amines, and the possible use of these agents in the treatment of psychiatric disorders, we have attempted to develop simple pharmacological procedures for evaluating the mono-amine oxidase inhibitory activity of new drugs by assessing their ability to potentiate some actions of tryptamine.Several known inhibitors of mono-amine oxidase were compared for their ability to (i) inhibit the mono-amine oxidase activity of a rat brain mitochondrial preparation in vitro; (ii) potentiate the action of tryptamine on the isolated rat fundal strip preparation; and (iii) potentiate the acute toxicity of tryptamine in mice.