MIF-1

This work describes the synthesis and pharmacological evaluation of picolinoyl-based peptidomimetics of melanocyte stimulating hormone release inhibiting factor 1 (MIF-1) as dopamine modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at dopamine D2 receptors (D2R). Methyl picolinoyl-l-valyl-l-alaninate (compound 6b) produced a statistically significant increase in the maximal [3H]-NPA response at 0.01 nM (11.9 ± 3.7%), which is close to the effect of MIF-1 in this assay at same concentration (18.3 ± 9.1%). Functional assays measuring cAMP mobilization in the presence of dopamine corroborate the activity of peptidomimetic 6b as a positive allosteric modulator (PAM) of D2R. In this assay, 6b produced a typical bell-shaped dose-response curve similar to that of the parent neuropeptide (18.3 ± 7.1% for 6b vs 15.4 ± 5.5% for MIF-1, both at 0.1 nM). Dose-response curves for dopamine in the presence of 6b show EC50 (0.33 ± 0.21 μM for 6b vs 0.17 ± 0.07 μM for MIF-1) and Emax (86.0 ± 5.4% for 6b vs 93.6 ± 4.4% for MIF-1) comparable to those of MIF-1, both at 0.01 nM. Furthermore, peptidomimetic 6b was tested for agonist activity at the human D2R and the results show that it displays no intrinsic agonism effect, endorsing its activity as a PAM of D2R. Cytotoxic and neurotoxic assays were performed for peptidomimetic 6b using HEK 293T cells and cortex neurons from 19 day old Wistar-Kyoto rat embryos, respectively, suggesting this analogue displays no toxicity effect in these assays up to 100 μM. Conformational energy minimization for 6b shows that this peptidomimetic cannot adopt the postulated type-II β-turn bioactive conformation, endorsing the possibility of an extended bioactive conformation as claimed by other researchers as a second bioactive conformation of MIF-1. Overall, the pharmacological and toxicological profile of peptidomimetic 6b together with its favorable druglike properties and structural simplicity makes it a potential lead compound for further development and optimization.

In this double-blind pilot study, 20 significantly depressed patients who all met the DSM-III R criteria for major depression were given a single subcutaneous injection of either 10 mg MIF-1 (Pro-Leu-Gly-NH2) or placebo on each of 5 consecutive days. Treatments were reversed for a second week of 5 consecutive daily injections. At the end of the first week, the group receiving MIF-1 was significantly improved on all rating scales as compared with the group receiving placebo. Eight out of 9 patients receiving MIF-1 showed marked improvement (score < or = 7 on the Hamilton Scale) as compared with only 2 of 11 patients receiving saline (P < 0.01). Administration of MIF-1 during the second week to the patients who had received placebo during the first week resulted in substantial improvement so that by the end of the second week the two groups were indistinguishable.

This work describes the synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D2 modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at D2 receptors (D2R). In this series, 2-furoyl-l-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPA response at 10 pM (11 ± 1%), comparable to the effect of MIF-1 (18 ± 9%) at the same concentration. This result supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds are tolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a using cortex neurons from 19-day-old Wistar-Kyoto rat embryos suggest that 6a displays no neurotoxicity up to 100 μM. Overall, the pharmacological and toxicological profile and the structural simplicity of 6a makes this peptidomimetic a potential lead compound for further development and optimization, paving the way for the development of novel modulating agents of D2R suitable for the treatment of CNS-related diseases. Additionally, the pharmacological and biological data herein reported, along with >20 000 outcomes of preclinical assays, was used to seek a general model to predict the allosteric modulatory potential of molecular candidates for a myriad of target receptors, organisms, cell lines, and biological activity parameters based on perturbation theory (PT) ideas and machine learning (ML) techniques, abbreviated as ALLOPTML. By doing so, ALLOPTML shows high specificity Sp = 89.2/89.4%, sensitivity Sn = 71.3/72.2%, and accuracy Ac = 86.1%/86.4% in training/validation series, respectively. To the best of our knowledge, ALLOPTML is the first general-purpose chemoinformatic tool using a PTML-based model for the multioutput and multicondition prediction of allosteric compounds, which is expected to save both time and resources during the early drug discovery of allosteric modulators.

In the present paper, the effect of simultaneous treatment of rats with low doses of MIF-1 and tricyclic antidepressants on rat behavior in the forced swim test was studied. It was found that MIF-1 stimulated in a dose-dependent manner "active" behavior of animals in this paradigm. The effect of MIF-1 appeared to be independent of changes in rats' locomotion in the open field test. The combined treatment of rats with MIF-1 (0.01 mg/kg IP) and amitriptyline (5 mg/kg IP) or desipramine (1.25 mg/kg) IP) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drugs given separately. The present data suggest the potential clinical efficacy of a combined therapy of depressive patients with MIF-1 and small doses of tricyclic antidepressants.

Prolyl-leucyl-glycinamide (MIF-1) has been observed to inhibit the analgesic effect of morphine in a series of animal studies. In the present study, the naloxone-like properties of MIF-1 were assessed in human subjects. Eight men received a capsule containing 60 mg of MIF-1 or placebo followed one hour later by a 10 mg intramuscular injection of morphine in a double-blind, crossover design at two visits 4 weeks apart. Experimental pain was induced by the cold pressor test administered 45, 75, 120 and 180 min after the morphine. Each subject recorded severity of pain on a 100 mm line scale every 5 sec during the 120 sec his foot was immersed in the cold water tank and during the 60 seconds immediately following its removal. On a third visit, baseline values were measured in the absence of morphine, MIF-1 or placebo. Analysis of variance revealed that MIF-1 resulted in significantly higher scores (less analgesia) compared with placebo when measured at 45 and 75 min after morphine during the immersion phase and during all four times the subjects were evaluated during the removal phase. The results indicate that MIF-1 can act in humans as an opiate antagonist.

MIF-1, a synthetic tripeptide with MSH-release inhibitory properties, has been reported to improve symptoms of Parkinson's disease, attenuate levodopa-related dyskinesias and diminish the dyskinetic movements of Tardive dyskinesia. More recently, MIF-1 has been reported partially to protect against the nigro-striatal dopamine depleting effects of MPTP in mice, raising the possibility that it may exert protective effects against the development of Parkinson's disease. There is evidence to suggest that MIF-1 increases nigro-striatal dopaminergic activity, but its ability to improve symptoms in patients with Parkinson's disease, levodopa-related dyskinesias and Tardive dyskinesia cannot be explained solely on the basis of the drug's effect on striatal dopaminergic neurons. MIF-1 has been reported to potentiate the melanocyte-lightening effect of melatonin in rats and its effects in patients with Parkinson's disease and Tardive dyskinesia are associated with marked mood elevation. It is, therefore, possible that the effects of MIF-1 in movement disorders are associated with increased melatonin secretion. Thus, hypothalamic MIF may modulate nigro-striatal dopaminergic functions in part via pineal melatonin. Such an interaction represents a novel mechanism by which hypothalamic peptides act to modulate the expression of movement disorders.