DEVELOPMENT OF AFFINITY LIGANDS FOR SIGMA RECEPTORS

σ受体最初被描述为一种亚型， 阿片受体介导某些合成的致幻作用 苯并吗喃类阿片类药物。 而假定的行为效应 σ受体活性药物已经相对较好地表征， 很难通过体外受体来表征σ受体 绑定实验 这是由于缺乏选择性的药物配体 不与其他（μ、δ、κ）阿片受体发生交叉反应。 我们 最近发现了一类新的高度选择性和有效的西格玛 受体活性药物。 我们制备了氚标记的 这些化合物之一（[3 H] 1，3-二邻甲苯基胍）（[3 H]DTG）。 使用 这种新型的选择性σ受体配体，我们已经进行了广泛的研究， σ受体的药物选择性的表征研究， 在脑组织中的分布 我们发现sigma受体不 只绑定所有致幻苯并吗喃类药物，但它也 与大多数抗精神病药物，特别是 氟哌啶醇 这种药物选择性特征使得σ受体是一种良好的受体。 可能与精神疾病的生化起源有关， 尤其是精神分裂症。 σ受体的纯化和 克隆它的基因可能会为我们了解甚少的 精神疾病的生化基础领域。 在这个应用程序中，我们 申请资金用于开发DTG的烷基化衍生物， 用[3 H]或125 I放射性标记。 我们打算用这些 烷基化衍生物作为亲和配体以共价标记σ 脑细胞膜中的受体。 放射性标记， σ受体的不可逆配体将极大地促进其 从脑膜提取物中纯化。

The sigma receptor was originally described as one of the subtypes of the opioid receptors mediating the hallucinogenic effects of certain synthetic benzomorphan type opiate drugs. While the behavioral effects of putative sigma receptor active drugs have been relatively well characterized, it has been difficult to characterize the sigma receptor by in vitro receptor binding experiments. This is due to the lack of selective drug ligands that do not crossreact with other (mu, delta, kappa) opioid receptors. We have recently discovered a new class of highly selective and potent sigma receptor active drugs. We have prepared a tritium labeled derivative of one of these compounds ([3H]1,3-di-o-tolyl-guanidine) ([3H]DTG). Using this novel, selective sigma receptor ligand we have performed extensive characterization studies on the drug selectivity of the sigma receptor and on its distribution in brain tissue. We find that the sigma receptor not only binds all hallucinogenic benzomorphan type drugs, but that it also binds with high affinity most antipsychotic drugs, particularly haloperidol. This drug selectivity profile makes the sigma receptor a good candidate to be involved in the biochemical origin of mental illness, particularly schizophrenia. The purification of the sigma receptor and the cloning of its gene may provide new insights into the poorly understood area of biochemical basis of mental illness. In this application we are requesting funds for the development of alkylating derivatives of DTG that are radioactively labeled with either [3H] or 125I. We intend to use these alkylating derivatives as affinity ligands to covalently label the sigma receptor in brain membranes. Availability of a radioactively labeled, irreversible ligand for the sigma receptor will greatly facilitate its purification from brain membrane extracts.