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Dual Effect Elicited by (Tyr~6)-γ2-MSH-6-12, and in Vivo Hyperalgesia Activity of Position 6-substituted Analogs Synthesis of Pharmaceutical Excipients Mono-O-(3-cholesteryloxycarbonyl) Propionyl Poloxamers

Author: WeiChunZuo
Tutor: DongShouLiang
School: Lanzhou University
Course: Biochemistry and Molecular Biology
Keywords: rMrgC (Tyr~6)-γ2-MSH-6-12 hyperalgesia analgesia non-canonical amino acids polyethylene glycol poloxamers cholesterol
CLC: R914
Type: Master's thesis
Year: 2009
Downloads: 20
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Abstract

Objective:Present study investigated the rMrgC agonist（Tyr⁶）-γ2-MSH-6-12’s physiology function on nociception in vivo by intrathecal administration;the non-canonical amino acids substituted Tyr⁶ to obtain analogs,further compared their potency to estimate the activate structure of（Tyr⁶）-γ2-MSH-6-12 and obtained optimized analogs,Provide theory evidence to study the function of Mrg receptors and the structure-activity relationship of（Tyr⁶）-γ2-MSH-6-12.Methods:Used the non-canonical aromatic amino acids 3-（1-naphtyl）-L-alanine（Nal）,4-fluoro-L-phenylalanine （（4-F）Phe）,4-methoxyl-L-phenylalanine（Mpa） and 3-nitryl-L-tyrosine （（3-NO₂）Tyr） to substituted（Tyr⁶）-γ2-MSH-6-12 in position 6.By way of intracellular calcium mobilization assay,we found two analogs:（Nal⁶）-γ2-MSH-6-12 and （Mpa⁶）-γ2-MSH-6-12,have same or high agonist activity compared toγ2-MSH-6-12. （Tyr⁶）-γ2-MSH-6-12 and its analogs were administrated by intrathecal injection in rats, and examined their hyperalgesia activity.Results:In rat tail-flick test we found （Tyr⁶）-γ2-MSH-6-12,previously thought to evoke pronociceptive effects in vivo after spinal administration,have dual effect on nociceptive:hyperalgesia at low concentration（0.5-20 nmol） and analgesia at high concentration（100-200 nmol）. （Tyr⁶）-γ2-MSH-6-12 at a high dose of 200 nmol increased the tail-withdrawal latency by 158%and 135%of basdine in the absence and presence of naloxone,respectively. The analogs（（4-F）Phe⁶）-γ2-MSH-6-12 and（（3-NO₂）Tyr⁶）-γ2-MSH-6-12,their hyperalgesia potency reduced most,（Nal⁶）-γ2-MSH-6-12 had same hyperalgesia potency asγ2-MSH-6-12.The best result was（Mpa⁶）-γ2-MSH-6-12,which showed greatly improved hyperalgesia potency,about more than 10 folds higher to （Tyr⁶）-γ2-MSH-6-12;higher metabolic stability,the hyperalgesia time prolonged from 20 min to 30-50 min;and more excellent receptor agonist specificity compared to （Tyr⁶）-γ2-MSH-6-12.Conclusion:（Tyr⁶）-γ2-MSH-6-12 had dual effect on nociception;activated rMrgC receptors in acute isolated DRG sensory neuron cells, decreased the intracellular calcium concentration;non-canonical amino acids modified resulted high activity,long time,and increased specificity analog: （Mpa⁶）-γ2-MSH-6-12. The conjugation of cholesterol to polyethylene glycol and poloxamers with succinate should improve its hydrophilicity and result in its amphiphilic.Methods: cholesterol was coupled with polyethylene glycol and poloxamers via dicarboxylic acid bridge with succinic acid and acid absorbent with triethylamine.Then chemical structures of products were tested by Fourier transform infrared spectroscope and 400 MHz nuclear magnetic resonance spectrameter.Results:Both products were soluble in water,methanol,ethyl acetate,but insoluble in petroleum ether.Conclusion:Present study used simple procedure to get high yield,good quality and amphaipathy products; Provide simple and easy methods to synthesize this kind of pharmaceutical excipients.

Dual Effect Elicited by (Tyr~6)-γ2-MSH-6-12, and in Vivo Hyperalgesia Activity of Position 6-substituted Analogs Synthesis of Pharmaceutical Excipients Mono-O-(3-cholesteryloxycarbonyl) Propionyl Poloxamers

Abstract

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