Structure-function relationships of somatostatin analogs.

Objective of peptide chemistry has always been the production of analogues for clinical application. Advantages sought over natural peptides are (a) reduced molecular size; (b) prolonged biological half-life, and (c) enhanced specificity. After elucidation of the active core of somatostatin a number of analogues have been synthetized.

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.

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.

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.

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.