• Archives of Pharmacal Research
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• 제22권2호
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• pp.184-188
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• 1999

A series of 4-amino Capsaincin anallogs 15, 17 and 19 were prepared to investigate the bioisosteric effect of 4-amino group, and all these compounds exhibited moderate or weak potency from their analgesic test. From our previous results and others, 4-hydroxyl group as well as 3-methoxy substituent could be crucial for high analgesic activity. This biological results also shows that the activity is sensitive to alkyl chain length in hydrophobic region and the phenylacetic amides 19 are more active than the corresponding urea derivatives 17.

• Archives of Pharmacal Research
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• 제22권2호
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• pp.165-172
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• 1999

In the present work , the transport mechanism of a capsaicin derivative, DA-5018, through blood-brain barrier (BBB) has been investigated to evaluate the feasibility of potential drug development. The result of pharmacokinetic parameters obtained from the intravenous injection of plasma volume marker,$[3^H]RSA$ and $[{14}^C]DA-5018$, indicated that both AUC, area under the plasma concentration curve and VD, volume of distribution in brain of $[3^H]RSA$ agreed with those reported ($1620{\pm}10 $percentage injected dose minute per milliliter (%IDmin/ml) and $12.0{\pm}0.1{\mu}l/g$, respectively). Elimination half-life and AUC of $[{14}^C]DA-5018$is corrected by the PHLC analysis, 19.6$\pm$1.2 min and 7.69$\pm$0.85% IDmin/ml, respectively. The metabolic rate of $[{14}^C]DA-5018$was very rapid. The blood-brain barrier permeability surface area (PS) product of $[{14}^C]DA-5018$ was calculated to be 0.24$\pm$0.05 $\mu$l/min/g. The result of internal carotid artery perfusion and capillary depletion suggested that [14C]DA-5018 pass through BBB with the time increasingly. Investigation of transport mechanism of $[{14}^C]DA-5018$ using agonist and antagonist suggested that vanilloid (capsaicin) receptor did not exist in the BBB, and nutrient carrier system in the BBB has no effect on the transport of DA-5018. In conclusion, despite the fact that penetration of DA-5018 through BBB is significant, the intact drug found in the brain tissue is small because of a rapid metabolism. Therefore, for the central analgesic effect of DA-5018, the method to increase the metabolic stability in plasma and the brain permeability should be considered.