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Substance P: structural requirements for the activation of brain catecholamine synthesis and locomotor activity in rats.

Intracerebroventricularly administered Arg-Pro-Lys-Pro-Gln-Gln-Phe-Gly-Leu-Met-NH2 (substance P, SP) enhanced the accumulation of DOPA after inhibition of the aromatic L-amino acid decarboxylase in the rat brain. SP also stimulated locomotor activity in a dose-dependent manner. A total of 31 structural analogues of SP were evaluated with respect to the action on brain monoamine synthesis as well as on locomotor activity. Catecholamine synthesis: SP1-10 was inactive which indicated that the [Met11]-NH2 terminal is essential for biological activity; [Leu10], [Phe7] and [Gln6] were also essential for activity; the minimum length requirement for activity was a hexapeptide amide structure. D-Amino acids in positions 8 or 9 increased activity. [D-Pro2]p-SP and [pGlu5, Gly7]-SP5-11 were active in the dopamine-rich areas, but inactive in the noradrenaline (norepinephrine)-predominant parts of the brain. The inactive [Ile7]-SP potentiated the effect of SP. Neither SP nor its analogues, with the exception of [Lys5,D-Leu8,D-Phe9]-SP5-11, increased the synthesis of 5-hydroxytryptophan (5-HTP). Locomotor activity: SP1-10 and [D-Phe9]-SP were as active as SP; [Ile7]-SP and [Ile7, Ile8]-SP were inactive and they did not antagonize the effect of SP. The results indicate that after chemical manipulation of the SP molecule it is possible to obtain great variation in activity and to dissociate to some extent the behavioural effects from those on brain catecholamine synthesis.