The present study was undertaken to investigate the mechanistic role of

The present study was undertaken to investigate the mechanistic role of L-prolyl-L-leucyl-glycinamide (PLG) in modulating agonist binding to the dopamine D2L receptor. bands at 51 kDa. Furthermore, PLG is definitely shown to compete with 1b for binding to the dopamine D2L receptor as determined by autoradiography, as well as competition experiments with PLG and 1a. Collectively, these findings suggest the successful development of GDC-0152 supplier a photoaffinity labeling agent, compound 1b, that has been used to elucidate the connection of PLG specifically with the dopamine D2L receptor. Keywords: Dopamine D2 receptor, L-Prolyl-L-leucyl-glycinamide (PLG), melanocyte-stimulating hormone (MSH) inhibiting element-1 (MIF-1), allosteric, autoradiography, peptidomimetic 1. Intro The tripeptide L-prolyl-L-leucyl-glycinamide (PLG, Fig 1), also known as melanocyte stimulating hormone launch inhibiting element (MIF-1), is an endogenous mind peptide that has been implicated in modulating dopaminergic neural transmission in the nigrostriatal pathway (Reed et al., 1994; Srivastava et al., 1988). Studies have shown that PLG does not modulate dopaminergic neurotransmission by influencing dopamine synthesis, uptake, or rate of metabolism; rather it functions through a mechanism in which PLG renders the dopamine receptor more responsive to agonists. PLG offers been shown to enhance the binding of various agonists such as apomorphine, 2-amino-6,7-dihydroxy-1,2,3,4,-tetrahydronaphthalene (ADTN), and N-propylnorapomorphine (NPA) to striatal dopamine receptors, without altering antagonist binding (Bhargava, 1983; Srivastava et al., 1988). Moreover, GDC-0152 supplier a previous study with bovine striatal synaptosomal membranes showed that PLG and its peptidomimetics show their very best modulatory effect on the dopamine D2L receptor subtype (Verma et al., 2005). Fig 1 Constructions of chemical compounds PLG offers ZC3H13 been shown to possess a variety of pharmacological activities in the central nervous system (Drucker et al., 1994; Hara and Kastin, 1986a; Hara and Kastin, 1986b; Mishra et al., 1983; Reed et al., 1994; Saleh and Kostrzewa, 1989; Srivastava et al., 1988). A series of earlier clinical studies demonstrated that this tripeptide offers substantial restorative activity in the treatment of Parkinsons disease, antipsychotic drug-induced tardive dyskinesia, and major depression (Barbeau, 1978; Ehrensing et al., 1977; Ehrensing et al., 1994). Although PLG is known to attenuate some symptoms of Parkinsons disease (Barbeau, 1975; Kastin and Barbeau, 1972) and tardive dyskinesia (Ehrensing et al., 1977), its short biological half-life offers limited its medical effectiveness (Mishra et al., 1997). Consequently, a number of conformationally constrained analogues of PLG have been designed with improved pharmacological properties (Mishra et al., 1997). Despite the years of study carried out on PLG and its dopaminergic modulatory effects, the mechanistic action of this tripeptide is still unfamiliar. It has been suggested that PLG functions similar to an allosteric modulator (Costain et al., 1999). Support for this type of hypothesis was based upon the fact that PLG increases the affinity of the dopamine receptor for its agonist, but it does not behave like an agonist itself (Chiu et al., 1981). However, such activity is also consistent with a mechanism by which PLG interacts with an independent macromolecule that is somehow coupled with the dopamine receptor. In order to determine the PLG binding site and to shed light on its mechanism GDC-0152 supplier of action, we previously designed and synthesized a family of photoaffinity-labeling providers utilizing like a template the potent PLG -lactam peptidomimetic, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA, Fig 1) (Fisher et al., 2006). The results from this study provided strong support for the binding of these photoaffinity-labeling providers at the same modulatory site as PLG and its peptidomimetics. In the present study, the photoaffinity labeling agent, 3(R)-[(4(S)-(4-azido-2-hydroxy-5-iodo-benzoyl) amino-2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide hydrochloride (1b, Fig 1) has been used in bovine striatal membranes to demonstrate that it is the dopamine D2L receptor with which the PLG peptidomimetic photoaffinity-labeling agent, and thus PLG, interacts. 2. MATERIALS AND.

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