MODULATION OF DOPAMINERGIC NEUROTRANSMISSION IN THE 6-HYDROXYDOPAMINELESIONED ROTATIONAL MODEL BY PEPTIDOMIMETIC ANALOGS 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 fou nd to have the ability to modulate dopamine D-2-receptor agonist bindi ng both in the striatum and limbic regions. In the present study the 6 -hydroxydopamine unilateral lesion model of apomorphine-induced rotati onal behaviour, in Wistar rats, was used to assess the dopaminergic mo dulatory activity of PLG and two novel analogues, L-prolyl-L-prolyl-L- prolinamide (analogue A) and o)]-8-oxo-4-thiabicyclo[3.3.0]octane-2-ca rboxamide (analogue B). PLG and the two novel analogues showed a bell- shaped dose-response relationship, suggesting that analogue A, B and P LG all manifest their effect through a similar mechanism and exhibit a window of therapeutic efficacy. Analogue A was a 100 times, while ana logue B was IO times, more potent than PLG in increasing the contralat eral rotational response when given in combination with apomorphine. A nalogue A was also more efficacious than PLG or analogue B at increasi ng apomorphine-induced contralateral rotations. Intrastriatal administ ration of either analogue A or B resulted in a greater increase in apo morphine-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 activi ty and may be possible therapeutic agents for the treatment of Parkins onian symptoms as well as tardive dyskinesia.