Pole-Jumping activity

Suggestion for conformation at the receptor site for pole-jumping activity... 

For activity of ACTH-derived peptides at the receptor for pole-jumping activity, the basic requirement seems to be the presence of a Phe and Met residue in close proximity. It is interesting to see that Phe and Met are close together in an a-helical structure in ACTH peptides (and as intra-chain neighbours in Met-enkephalin) and in the crystalline state in ACTH-(4-10) as a 3-pleated sheet and in ACTH-(4-7) in the form of a horseshoe this close proximity is in line with the results of a Free-Wilson type of analysis. 

The first step in these studies has been the search for the shortest fragment of the ACTH chain that is essential for (maintenance of) activity. Next, changes in the peptide backbone and modification of the side-chains of the amino acid residues have been studied. As a test system the delay of extinction of an active avoidance response in rats as measured in a pole-jumping test after subcutaneous administration has been used (7 ) this assay method gives a graded dose-response relationship which allows the estimation of an ED50 and thus potency ratio s. The heptapeptide ACTH--(4-10) has been used as the reference peptide (8 ). For a more extensive review see ref. 9. 

Suggested preferred conformations can be fixed by cyclization. Cystine has been used to obtain cyclic analogues of Org 2766 viz. H-Cys-Glu-His-Cys-D-Lys-Phe-OH, H-Cys-Ala-Ala-Cys-D-Lys--Phe-OH and H-Cys-Ala-Ala-Phe-D-Lys-Cys-OH (patent application 0052028 of Roussel-UcIaf), and the peptides were tested for activity in the pole-jumping test. Unfortunately, one cannot conclude from their data if cyclization has resulted in an increase or decrease in activity since no reference peptide has been included to compare potencies. In the literature cyclization of [Lys ]ACTH--(5-10) (the COOH group of Gly with the 6-NH2 function of Lys ) has been reported the resulting peptide was inactive in steroidogenesis (61). Increase of the ring size with three atoms (a Gly residue), however, resulted in a peptide that was more active... 

In H-Met(02)-Glu-His-Phe-D-Lys-Phe-0H (Org 2766), the large increase in activity in the pole-jumping test and the longer duration of action can only partly be explained by an increase in stability. It is suggested that in the form of an a-helix or loop-1 ike structure at the receptor site, the presence of D-Lys as well as Met(02)" and Phe contributes to an increase of receptor affinity. 

If in instrumental conditioning a response is not followed by a punishment, but its absence, animals will increase this response in order to minimise punishment. In active avoidance tasks, for instance, animals have to show a distinct behavioural response in order to avoid a punishment. Typical examples would be shuttle-box experiments and jump-up avoidance. A shuttle box consists of two compartments that are connected by a sliding door. The punishment will be signalled by either a tone or a light stimulus (CS). Animals have to leave the compartment in which the CS was presented within a selected amoimt of time, after which the CS would be followed by a footshock. In the pole-jump test, the occurrence of the footshock will be signalled by a tone or hght stimulus as well. Animals can avoid the punishment if they jump onto a vertical wooden rod. 

Perhaps the oldest animal model to predict potential antipsychotic drug efficacy is the conditioned avoidance response (CAR) (108, 112, 181, 182). In the conditioned reinforcement model, experimental animals are trained to perform a certain response to avoid a mild shock. Trained avoidance responses may be active (pressing a lever, climbing a pole, or jumping out of a box) or passive (remaining in the darker of two compartments). Classical antipsychotic drugs and benzodiazepines reduce avoidance responding at doses that do... 

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