A series of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamides was synthesized, starting from the 2,6-dimethoxybenzoic acids, by boron tribromide demethylation of the corresponding 3,5-disubstituted 2,6-dimethoxybenzamides and separation of the two positional isomers. The correct structure assignments were based on selective decoupling studies on their 13C NMR spectra. The salicylamide derivatives were tested for antidopamine activity in vivo by their ability to inhibit the apomorphine syndrome in the rat and in vitro by their ability to displace [3H]spiperone from striatal preparations of the rat brain. The activity seems to reside exclusively in the S enantiomer. Several compounds were considerably more potent than haloperidol, particularly those having an ethyl group in the 3-position and a halogen atom in the 5-position of the aromatic ring. The corresponding 5-alkyl-3-halogen-substituted compounds were much less active. A low acute toxicity was found for the most potent compounds. Some of the salicylamides displayed a 10-20-fold separation between the dose which blocks apomorphine-induced hyperactivity and that which blocks apomorphine-induced stereotypy. One compound, S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide (raclopride, FLA 870) (13) had a stereotypy--hyperactivity separation more than twice that of sulpiride while being 100 times more potent in blocking the apomorphine effects. On this basis, 13 was selected for clinical trials against schizophrenia.

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1. Heparin was prepared from mouse mastocytoma tissue by mild procedures, including extraction of mast-cell granules with 2m-potassium chloride, precipitation of the extracted polysaccharide with cetylpyridinium chloride from 0.8m-potassium chloride and finally digestion of the isolated material with testicular hyaluronidase. The resulting product (fraction GEH) represented approx. 40% of the total heparin content of the tissue. 2. Fraction GEH was fractionated by gel chromatography on Sepharose 4B into three subfractions, with average molecular weights (¯Mw) of approx. 60000–70000 (highly polydisperse material), 26000 and 9000 respectively. Treatment of each of the subfractions with alkali or with papain did not affect their behaviour on gel chromatography. Amino acid and neutral sugar analyses indicated that the two low-molecular-weight fractions consisted largely of single polysaccharide chains lacking the carbohydrate–protein linkage region. It was suggested that these heparin molecules had been degraded by an endopolysaccharidase. 3. Pulse labelling in vivo of mastocytoma heparin with [35S]sulphate showed initial labelling of large molecules followed by a progressive shift of radioactivity toward fractions of lower molecular weight. Further, heparin-depolymerizing activity was demonstrated by incubating 35S-labelled heparin in vitro with a mastocytoma 10000g-supernatant fraction. Appreciable degradation of the polysaccharide occurred, as demonstrated by gel chromatography. In contrast, no depolymerization was observed on subjecting 14C-labelled chondroitin sulphate to the same procedure.

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Zimelidine (ZIM) and its main active metabolite norzimelidine (NZIM) have been shown to preferentially inhibit 5‐hydroxytryptamine (5‐HT) neuronal uptake both in vitro and in vivo while having much less effect on noradrenaline (NA) uptake. ZIM in vivo blocked the 5‐HT uptake mechanism in the cerebral cortex, hippocampus, striatum, hypothalamus and spinal cord, thus indicating effects on both the ascending and descending 5‐HT pathways. ZIM is devoid of a 5‐HT releasing action, MAO‐inhibitory properties and effects on dopamine (DA) uptake. ZIM failed to reduce NA turnover even in high doses, but markedly reduced 5‐HT turnover in very low doses in the rat. ZIM also enhanced 5‐HT mediated behaviours in mice in doses related to the inhibition of 5‐HT uptake. In contrast to amitriptyline (AMI) and mianserin (MIAN), ZIM only in extremely high doses displayed a 5‐HT receptor blocking action in vitro and failed to block 5‐HT mediated behaviour. ZIM was practically devoid of action on histamine H1 and H2 receptors, and had also a neglible action on noradrenergic α1‐ and α2‐receptors, and on β‐receptors. Unlike the tricyclic antidepressants (TAD's) ZIM had a negligible action on muscarinic receptors and failed to affect cholinergic induced activity. Long‐term treatment with ZIM did not result in any attenuation of the 5‐HT uptake blocking potency or the reduction of 5‐HT turnover. This long‐term treatment slightly reduced the number of β‐receptors in the brain. However, repeated ZIM‐treatment induced a new 5‐HT receptor binding site characterized by a low affinity and with a high number of binding sites and decreased the number of high affinity 5‐HT receptor binding sites. Unlike the TAD's zimelidine failed to block the action of reserpine. Metabolic and behavioural interaction studies in mice showed that ZIM was devoid of any significant interactions with ethanol, barbiturates and benzodiazepines. It is concluded that ZIM markedly differs front both the TAD's and new antidepressants such as mianserin and nomifensine. ZIM seems preferentially to effect the presynaptic 5‐HT reuptake mechanism while having a negligible action on noradrenergic, 5‐HT, acetylcholine and histamine receptors in the brain.