Chemistry and pharmacology of SMS 201-995, a long-acting octapeptide analogue of somatostatin.

Starting from a hypothetical conformation of natural somatostatin and a knowledge of the minimal fragment needed for biological activity, a process of rational design and lead optimization has led to the potent, selective, and long-acting analogue SMS 201-995, (formula: see text) which selectively inhibits growth hormone secretion in several animal species for up to 6 h after subcutaneous application. In the rat, SMS inhibits GH, insulin, and glucagon 70, 3, and 23 times more potently than SRIF, resulting in GH/insulin and GH/glucagon selectivities of 20 and 3, respectively. The compound has been shown to inhibit growth of transplantable insulinomas in hamsters and to label selectively a subset of somatostatin receptors in the rat cortex. A radioactively labelled analogue has been used to visualize somatostatin receptors in a GRF-secreting human tumour. The stability and duration of action of SMS 201-995 after subcutaneous injection enable for the first time extended investigations of the clinical utility of somatostatin in various diseases.

Octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine.

A synthesis of all four diastereoisomeric 3-(tert-butoxycarbonyl)-1,6-dimethoxyoctahydrobenzo[g]quinolines 13a-d is presented. The two trans isomers 13b and 13c have been converted to tricyclic analogues 20 (CV 205-502) and 26 (205-503) of the potent dopaminomimetic ergolines CQ 32-084 and pergolide, respectively. These two compounds combine the essential moiety of apomorphine with the important 8-substituents of ergolines. Preliminary pharmacological evaluation of 20 and 26 suggests that these novel dopamine agonists combine the specificity of apomorphine with the potency, long duration of action, and good oral activity of the ergolines.

Synthesis and pharmacological studies of 4,4-disubstituted piperidines: a new class of compounds with potent analgesic properties.

A series of 4,4-disubstituted piperidines has been synthesized and evaluated for analgesic activity. Several of these analogues show analgesic potency comparable to morphine in the mouse writhing and tail-flick tests. A number of compounds exhibit high affinity for [3H]naloxone binding sites in rat brain membranes. Among the most potent derivatives are compounds 15 and 48. Although opiate-like, attempts to modify this activity with various substituents have failed to produce antagonistic properties. A few of these analogues also show marked long-lasting serotonin antagonism in the guinea pig serotonin toxicity test and the DL-5-hydroxytryptophan induced head-twitch model in the mouse.

Unexpected opioid activity in a known class of drug.

Tifluadom, although structurally a 1,4 benzodiazepine, has no affinity for the 3H-flunitrazepam binding site, but is a potent displacer of 3H-bremazocine from its opioid binding site. Tifluadom is characterised as an opiate kappa-receptor agonist in vitro and in vivo with potent analgesic activity in animals and no dependence potential.

SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action.

Stepwise modification of a conformationally stabilised analogue of the fragment of somatostatin which had been thought to be essential biologically active moiety has enabled us to synthesise the analogue H-(D) Phe-Cys-Phe-(D) Trp-Lys-Thr-Cys-Thr(ol) code-named SMS 201-995, which in vitro is three times more potent than the native hormone in inhibiting the secretion of growth hormone, which is highly resistant to degradation by pure enzymes and by tissue homogenates, which in vivo in rat and rhesus monkey is (depending on test system) at least 20 times more active than somatostatin, which is much longer acting, and which moreover in both species is much more selective in inhibiting the secretion of growth hormone than that of insulin. The compound is active by several routes of administration including the oral, is well tolerated both in laboratory animals and in man, and is currently undergoing preliminary clinical trial.

Tetronomycin, a novel polyether of unusual structure.

Tetronomycin, C34H50O8, isolated from a strain of Streptomyces sp. nov. represents a novel polycyclic ionophore polyether. The crystal structure and absolute configuration were established by X-ray analysis of the mono-O-acetyltetronomycin silver salt. Tetronomycin is the first metabolic polyether which contains a tetronic acid moiety instead of the essential carboxylic acid function. A trisubstituted cyclohexane ring and an interesting molecular conformation of the silver salt represent additional unique structural features. Extensive NMR-studies enabled the assignment of chemical shifts and the correlation of the proton and carbon signals. Tetronomycin exhibits activity against Gram-positive bacteria.

Conformations and biological properties of apomorphine and its phenanthro(10,1-b,c)azepine homologue.

11,12-Dihydroxy-7-methyl-4,5,6,7,7a,8-hexahydrophenanthro[10,1-b,c]-azepine (2), a homologue of apomorphine (1), has been found to be devoid of dopaminergic effects. The biological differences between apomorphine and this homologue are explained in terms of differences in conformation of the two molecules.

Stereochemistry of a curare alkaloid: O,O',N-trimethyl-d-tubocurarine.

The three-dimensional structure of O,O',N-trimethyl-d-tubocurarine, a neuromuscular blocking agent, has been determined by x-ray crystallography. This may help to provide insight into its pharmacologic action.