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Synthesis and neuromodulatory effects of TRH-related peptides: inhibitory activity on catecholamine release in vitro

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Abstract

Background

A detailed comprehension of central mechanisms underlying feeding behavior holds considerable promise for the treatment of alimentary disorders.

Methods

In order to elucidate the tight interrelationships occurring at the hypothalamic neuronal endings between aminergic neuro-transmitters and co-localized appetite modulators, we initially studied the effects of two anorexigenic peptides structurally related to thyrotropin-releasing hormone (TRH, 1), namely cyclo(His-Pro) (CHP, 2) and pGlu-His-Gly-OH (3), on [3H]-norepinephrine and [3H]-dopamine release from perfused rat hypothalamic synaptosomes. Furthermore, a number of TRH and CHP analogues were synthesized and tested for their ability to influence neurotransmitter release in the selected neuronal model.

Results

Peptide 3 showed only a slight inhibitory activity on norepinephrine release, whereas no effect was observed for compound 2. TRH analogue 8, metabolically stabilized by the replacement of pyroglutamate with the pyrohomocysteic acid (pHcs), was found to be inactive. Conversely, a significant inhibitory effect on dopamine and norepinephrine release was observed for the CHP-related diketopiperazines cyclo(Leu-Pro) (11) and cyclo(His-Gly) (14).

Conclusions

These results suggest a potential role for cyclo-dipeptides 11 and 14 in the hypothalamic modulation of appetite suppressant circuitry.

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Abbreviations

AcOH:

acetic acid

Boc:

tert-butoxycarbonyl

DBU:

1,8-diazabicyclo[5.4.0.]undec-7-ene

DCC:

dicyclo-hexylcarbodiimide

DCM:

dichloromethane

DMF:

N,N-dimethylformamide

AcOEt:

ethyl acetate

Fmoc:

9-fluo-renylmethoxycarbonyl

MeOH:

methanol

NMM:

N-methyl-morpholine

OSu:

N-hydroxysuccinimide derivative

TEA:

triethylamine

TFA:

trifluoroacetic acid

THF:

tetrahydrofuran

Z:

benzyloxycarbonyl

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Authors and Affiliations

  1. Department of Pharmacy, G. d’Annunzio University, via dei Vestini 31, 66013, Chieti, Italy

    Luigi Brunetti, Annalisa Chiavaroli, Alessandra Cocco, Claudio Ferrante, Anna Ferrucci, Grazia Luisi, Giustino Orlando, Francesco Pinnen & Michele Vacca

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  1. Luigi Brunetti
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  2. Annalisa Chiavaroli
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  3. Alessandra Cocco
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  4. Claudio Ferrante
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  5. Anna Ferrucci
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  6. Grazia Luisi
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  7. Giustino Orlando
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  8. Francesco Pinnen
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  9. Michele Vacca
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Correspondence to Michele Vacca.

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Brunetti, L., Chiavaroli, A., Cocco, A. et al. Synthesis and neuromodulatory effects of TRH-related peptides: inhibitory activity on catecholamine release in vitro. Pharmacol. Rep 65, 823–835 (2013). https://doi.org/10.1016/S1734-1140(13)71063-6

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  • DOI: https://doi.org/10.1016/S1734-1140(13)71063-6

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