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Synthesis of thyrotropin-releasing hormone analogs. 1. Complete dissociation of central nervous system effects from thyrotropin-releasing activity
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1984
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Central Amino AcidAliphatic Amino AcidsMolecular PharmacologyMedicinal ChemistryNeuroendocrine MechanismHypothalamic PeptideNeurochemistryHealth SciencesBiochemistryNeuropharmacologyThyrotropin-releasing ActivityNervous SystemEndocrinologyPharmacologyNeurophysiologyPhysiologyComplete DissociationNeuropeptide ReceptorThyrotropin-releasing Hormone AnalogsNeuroscienceCentral Nervous SystemThyroid HormoneMedicineDrug DiscoveryNeuropeptides
Twenty-four thyrotropin-releasing hormone (TRH) analogues containing mainly aliphatic amino acids in position 2 were synthesized and tested for central nervous system (CNS) and hormonal (TSH) activity. Application of the pentafluorophenyl ester method in the syntheses resulted in optimal yields and high purity of the products. The neutral tripeptides pGlu- Nva -Pro-NH2 (9), pGlu-Nle-Pro-NH2 (10), and pGlu-Leu-Pro-NH2 (3) with a three- or four-membered straight or branched alkyl side chain in the position of the central amino acid had 2.5 to 10 times stronger anticataleptic effect than TRH, demonstrating that the presence of histidine is not essential for the CNS activity. Analogue 9 exhibited tenfold anticataleptic activity as compared to TRH, and it was found to be fully inactive in the release of TSH.