Goodman Allan, McCall Jennifer R, Jacocks Henry M, Thompson Alysha, Baden Daniel, Abraham William M, Bourdelais Andrea
Center for Marine Science, University of North Carolina Wilmington (UNCW), 5600 Marvin K. Moss Lane, Wilmington, NC 28409, USA.
Department of Research, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140, USA.
Mar Drugs. 2014 Mar 28;12(4):1839-58. doi: 10.3390/md12041839.
Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.
短裸甲藻毒素是一种由短裸甲藻产生的梯形框架聚醚。这种生物体还负责产生被称为短裸藻毒素的神经毒性化合物。摄入或吸入短裸藻毒素会导致诸如胃肠道疾病和支气管收缩等不良反应。短裸甲藻毒素对短裸藻毒素表现出拮抗作用，单独给药时显示出有益特性。例如，在哮喘绵羊模型中，短裸甲藻毒素已被证明能提高气管黏膜速度，这一特性使其有可能被开发用于治疗囊性纤维化。短裸甲藻毒素的作用机制尚不清楚，确切的结合位点也未阐明。为了进一步了解短裸甲藻毒素的作用机制并有可能开发第二代候选药物，通过修饰醛基部分制备了一系列短裸甲藻毒素衍生物。这些衍生物包括脂肪族、芳香族和杂芳香族酰肼衍生物。使用体外突触体结合试验对短裸甲藻毒素衍生物进行测试，以确定这些化合物从其天然受体上取代短裸藻毒素和短裸甲藻毒素的能力。使用绵羊吸入模型来确定滴注短裸甲藻毒素衍生物是否会导致支气管收缩。只允许进行小的修饰，较大的基团会导致对短裸甲藻毒素受体的亲和力丧失，并在绵羊模型中导致支气管收缩。
