Capsaicin 유도체의 최루성 평가 및 독성의 예측
Lachrymal Evaluation of Some Capsaicin Analogs and Their Predicted Toxicities
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초록
고추의 매운 성분으로서 몇 가지 Capsaicin 유도체(1-8)의 최루성 평가에 관한 정량적인 구조-활성관계(QSARs)와 독성을 이해하기 위하여, Capsaicins의 구조들과 Scoville hot units (SHU) 사이의 2DQSAR 모델을 유도하고 TOPKAT 및 ADME 방법으로 예측된 독성값들을 검토하였다. 시위 진압용 물대포 수용액의 주성분으로서 Nonivamide (6: PAVA spray)는 가수분해 생성물보다 높은 독성을 나타낼 것으로 예상되었다. 최적화된 2D-QSAR 모델(M2)은 통계적으로 양호하였을(r^2= 0.974) 뿐 아니라, logSHU(매운맛)의 97.4%를 설명하였으며 logSHU는 입체적인 요소로서 Capsaicin 분자내 alkyl group(X)의 폭(B_4)에 관한 적정값((B_4)_(opt.)= 9.735Å)에 의존적이었다. 예측된 피부 감작성(SI)과 경구독성(LD_(50); mg/kg)은화합물, 1>5>8의 순서로 강하였으며 Nonivamide(6)는 상대적으로 매우 낮았다. 그리고 ADME 예측결과, 화합물 NDOA(7)는 혈장 단백질 결합성(K_(hsa))과 뇌혈 분배계수(logBB)가 낮은 경향을 나타낸 반면에 Caco-2 및 Madin-darby canine kidney (MDCK) 세포 투과성(nm/sec.)은 다른 화합물보다 비교적 높은 값을 나타내었다. 그러므로 포괄적인 의미에서, 최루성 평가요소는 SHU를 위시하여 분자의 소수성(logP) 그리고 인체 유해성에 관한 급만성 독성과 ADME 자료가 포함되어야 할 것이다.
Abstract
To understand the quantitative structure-activity relationships (QSARs) on the lachrymal evaluation of some Capsaicin analogs (1-8) as the ingredient of spicy chile and their toxicities, derived 2D-QSAR models between Scoville hot units (SHU) and ligands of Capsaicins, and predicted toxicities by TOPKAT and ADME were discussed quantitatively. From the results, it was expected that the toxicity of Nonivamide (6; PAVA spray),the major ingredient in an aqueous solution of a riot-control water cannon, was higher than the toxicity of hydrolysis products. The statistical quality of the optimized 2D-QSAR model (2M) is good (r^2=0.974) and accounts for 97.4% of the variance in logSHU (Spicy heat). It was found that the logSHU values were dependent upon the optimal value ((B_4)_(opt.)=9.735Å) of alkyl substituents (X) width (B_4) as sterical factor. The predicted skin irritation (SI) and oral toxicity (LD_(50); mg/kg) of Capsaicins by TOPKAT the order of the compounds 1>5>8 strongly and that of Nonivamide (6) was relatively lower. And from the prediction of ADME, generally, compound NDOA (7) showed that the binding ability to blood plasma albumin (K_(hsa)) and the brain/blood partition coefficient (logBB) had a tendency to be low, whereas the Caco-2 and Madin-darby canine kidney(MDCK) cell permeability (nm/sec.) had higher values than the others. Therefore, comprehensively, starting with SHU, the molecular hydrophobicity (logP), some chronic and acute toxicity, and ADME data was shown to be detrimental to the human body as lachrymal evaluation factors will be forced to be included.
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