Modulation of dopaminergic neurotransmission in the 6-hydroxydopamine lesioned rotational model by peptidomimetic analogues of L-prolyl-L-leucyl-glycinamide

Melanocyte stimulating hormone release inhibiting factor (MIF-I), also known as L-prolyl-L-leucyl-glycinamide (PLG), has previously been found to have the ability to modulate dopamine D-2-receptor agonist binding both in the striatum and limbic regions. In the present study the 6-hydroxydopamine unilateral lesion model of apomorphine-induced rotational behaviour, in Wistar rats, was used to assess the dopaminergic modulatory activity of PLG and two novel analogues, L-prolyl-L-prolyl-L-prolinamide (analogue A) and (2S,5R,7R)-1-Aza-7[3'(S)-1-(2',5'-dioxo-pyrrolidino[2,1-c]piperazino)]-8-oxo-4-thiabicyclo[3.3.0]octane-2-carboxamide (analogue B). PLG and the two novel analogues showed a bell-shaped dose-response relationship, suggesting that analogue A, B and PLG all manifest their effect through a similar mechanism and exhibit a window of therapeutic efficacy. Analogue A was a 100 times, while analogue B was IO times, more potent than PLG in increasing the contralateral rotational response when given in combination with apomorphine. Analogue A was also more efficacious than PLG or analogue B at increasing apomorphine-induced contralateral rotations. Intrastriatal administration of either analogue A or B resulted in a greater increase in apomorphine-induced rotations than the most efficacious intraperitoneally delivered dose. The results of the present study suggest that PLG and its two novel analogues are able to modulate dopamine receptor activity and may be possible therapeutic agents for the treatment of Parkinsonian symptoms as well as tardive dyskinesia.