C. Melchiorre

Polymethylene tetramines: a new generation of selective muscarinic antagonists.

Abstract There is increasing evidence to support the existence of multiple subtypes of muscarinic receptors. However, the limited selectivity of available ligands has hampered their characterization. Carlo Melchiorre describes structure-activity relationship studies on a series of polymethylene tetramines which have led to the discovery of methoctramine, a potent and highly selective muscarinic antagonist structurally unrelated to all other known muscarinic agonists and antagonists. Methoctramine not only discriminates significantly between M 1 and M 2 receptors but also has remarkable selectivity for cardiac M 2 muscarinic receptors.

Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo

SummaryThe antimuscarinic effects of methoctramine (N, N′- bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine tetrahydrochloride), a polymethylene tetraamine endowed with high cardioselectivity in vitro, were assessed in two in vivo preparations. Methoctramine (300 μg/kg i.v.) strongly inhibited the methacholine- and muscarine-induced bradycardia in the anaesthetized and pithed rat, respectively. The same dose of methoctramine did not significantly affect the depressor action of methacholine in the anaesthetized rat mediated by vascular M2 receptors. Furthermore, even high doses of methoctramine (up to 1 mg/kg i. v.) did not reduce the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343 in the pithed rat. These data suggest that methoctramine while showing high affinity for cardiac M2α receptors has rather low affinity for ganglionic M1 and vascular M2 receptors. This in vivo study thus provides further evidence to support the view that methoctramine is a potent and highly selective antagonist of cardiac M2α receptors.

Benzisoxazole and benzisothiazole analogs of auxin

Abstract In order to ascertain to what extent benzisoxazole and benzisothiazole can substitute the indole nucleus in auxin, several benzisoxazole and benzisothiazole analogs of indole-3-acetic acid were synthesized and their activity as plant hormones tested. The results of the slit-pea-stem curvature test are reported; among other compounds, 5-chloro-1, 2-benzisothiazole-3-acetic acid was the most active, showing about 330 per cent of the activity of indole-3-acetic acid.

Thiol group may be involved in the irreversible blockade of presynaptic α2-adrenoreceptors by pyrextramine and benextramine in the isolated guinea pig ileum

This study, conducted on isolated guinea pig ileum, was designed to establish the mechanism of presynaptic alpha 2-adrenoreceptor blockade by the tetramine disulfides, benextramine and pyrextramine. At 1 microM these drugs irreversibly blocked norepinephrine (NE)-induced inhibition of the twitch response to electrical stimulation. This may be the result of covalent bond formation between the disulfide bridge of the inhibitor and a thiol function at the receptor level through an interchange reaction since the benextramine carbon analogue did not affect NE response under the same conditions. Furthermore, NE (10 microM) failed to protect presynaptic alpha 2-adrenoreceptors from pyrextramine blockade whereas idazoxan (O.T microM) completely abolished the irreversible antagonism of pyrextramine (1 microM). This finding suggests that the tetramine disulfide binding site may coincide with that of idazoxan and is different from the NE binding site.

Hypotensive effect in dogs and rats of intravenous injections of the α1-adrenoreceptor antagonist benoxathian

The hypotensive effect of the alpha 1-adrenoreceptor antagonist benoxathian has been evaluated in rats and dogs, in comparison to that evoked by WB 4101 and prazosin. In anaesthetized dogs, i.v. injection of benoxathian (25-100 micrograms/kg), WB 4101 (5-25 micrograms/kg) and prazosin (50 micrograms/kg) produced an immediate fall in diastolic blood pressure, which reached a maximum at about 30 sec after drug administration. Whereas the hypotensive effect of prazosin persisted up to 3 hr following injection, the effect of both benoxathian and WB 4101 completely disappeared after 30-60 min. The hypotensive effect of benoxathian was dose-dependent. Pressor responses to i.v. noradrenaline (5 micrograms/kg), adrenaline (5 micrograms/kg) and phenylephrine (20 micrograms/kg) were markedly inhibited (60-75%) by benoxathian (100 micrograms/kg) whilst the pressor response to angiotensin II (0.05 micrograms/kg) was not reduced, but indeed slightly increased. The hypotensive effect of benoxathian (100 micrograms/kg) was abolished following pre-treatment with prazosin (50 micrograms/kg) or hexamethonium (1000 micrograms/kg). In anaesthetized rats similar results were obtained although recovery in blood pressure from the initial drop after i.v. injection of the drugs was slower than in dogs. Benoxathian was slightly more toxic than WB 4101 in rats. In conclusion, present findings show that benoxathian causes a profound hypotensive effect in dogs and in rats through postsynaptic alpha-adrenoreceptor blockade; however its effect, as well as that of WB 4101, is shorter lasting than that of prazosin.

Cholinergic Compounds. IV,1 an Improved Synthesis of allo- and epi-Desethermuscarine

Abstract We have recently reported the synthesis of allo- and epi-dese-thermuscarine from 4t-methyl- and 4c-methyl-3c-hydroxy-1r-(N, N, -di-methylcarboxamido) cyclopentane, (II) and (III) respectively. Although this stereospecific synthetic route is simple in concept, it actually requires several steps to obtain II and III, and results in low yields.2

Synthesis and α-blocking activity of some analogues of idazoxan☆

Abstract Several analogues of idazoxan 1 and fenmetazole 2 were prepared as potential α 2 -adrenoreceptor antagonists. Their blocking activity and selectivity on α 1 - and α 2 -adrenoreceptors were evaluated in isolated rat vas deferens. Although all the drugs displayed a significantly lower activity compared to the parent compounds 1 and 2 , with 3 being the only exception, the present results might help in elucidating the role of ring oxygens of 1 in drug—receptor interaction.

Resolution of the potent α1-adrenoreceptor antagonist 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzoxathian (benoxathian)

Abstract The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzoxathian hydrochloride ( 1 : benoxathian) were prepared from the chiral 1,4-benzoxathian-2-carboxylic acids [(+)- and (−)- 3 ] which in turn were obtained through the resolution of the racemic acid with R - and S - α -methylbenzylamine. Their blocking activities and relative selectivities on α 1 - and α 2 -adrenoreceptors were evaluated on isolated rat vas deferens. For α 1 -adrenoreceptors the enantiomer (−)- 1 was 10 times more potent than the enantiomer (+)- 1 , whereas no significant difference between the blocking activity of the enantiomers was observed for α 2 -adrenoreceptors. Furthermore, the enantiomer (−)- 1 showed high activity and selectivity toward the α 1 -adrenoreceptor (p A 2 = 9.36; selectivity ratio = 1230) which may have relevance in the characterization of α-adrenoreceptor subtypes.

Cholinergic Compounds. VI. Synthesis of epiallo Desethermuscarine

Abstract Recently, the synthesis of desethermuscarine 1-3 and of two of its three possible isomers, allo– and epi– desethermuscarine, 4,5 was reported. These substances, having muscarinic activity, have shown to be extremely interesting in the study of the cholinergic receptor. As a result, the role of the ether oxygen in muscarinic activity appears to be revised. Yet, due to lack of data on the fourth isomer, a complete picture of the activity of these compounds is impossible to date.

A New Synthesis of 3-Methyl-3-cyclopentene-1-carboxylic Acid and Derivatives

Abstract Recently we reported the synthesis of desether-muscarine,1 a compound of interesting cholinergic activity. The starting material for this synthesis was the 3-methyl-3-cyclopentene-l-carboxylic acid (II) already synthesized through photochemical addition of ethyl diazoacetate to isoprene and subsequent pyrolisis of I 2 Following this synthetic route it was difficult to obtain such compound and mostly starting material was recovered together with a little photoaddition product. In order to have enough compound for the synthesis of desethermuscarine with the aim to separate its optical isomers, a new synthesis of I, from isoprene and ethyl diazoacetate via copper-catalized addition,3 has been sought and is reported here.