Campbell B G, Scherz M W, Keana J F, Weber E
Vollum Institute, Oregon Health Sciences University, Portland 97201.
J Neurosci. 1989 Oct;9(10):3380-91. doi: 10.1523/JNEUROSCI.09-10-03380.1989.
Sigma receptors are specific, highly localized binding sites in limbic and sensorimotor structures of the brain that interact with many psychotropic drugs. These agents include the psychotomimetic benzomorphan opiates, the psychotomimetic drug phencyclidine and its analogs, as well as numerous typical and atypical antipsychotics such as haloperidol, chlorpromazine, and the novel drugs BMY 14802 and rimcazole. So far, no physiological function has been assigned to these binding sites. We have synthesized a number of novel sigma receptor-active drugs derived from the selective sigma ligand N,N'-di(o-tolyl)guanidine (DTG). DTG and its congeners were found to inhibit contractions of the guinea pig ileal longitudinal muscle/myenteric plexus (LMMP) preparation evoked by electrical stimulation. In addition, the sigma ligands noncompetitively antagonized contractions of the LMMP preparation evoked by serotonin (5-HT). The 5-HT-evoked contractions were found to be largely due to 5-HT's activation of 5-HT3 receptors to release ACh. The activity of DTG congeners in inhibiting electrically or 5-HT-evoked contractions of the LMMP highly correlated with their potency to inhibit binding of both 3H-DTG and (+)3H-3-PPP [3(3-OH-phenyl)-N-(1-propyl)piperidine] to sigma receptors in guinea pig brain homogenates. Two DTG congeners that did not bind to sigma receptors also showed no activity in the bioassay. Many other (but not all) sigma receptor ligands showed a high correlation between their potency to inhibit electrically evoked contractions of the LMMP and their sigma receptor binding affinity. The benzomorphans (+)SKF 10,047 and (+)cyclazocine potentiated electrically evoked contractions of the LMMP. Sigma ligands also inhibited the contractions of the LMMP in the presence of the opiate antagonist naloxone and in preparations in which opioid receptors had been inactivated by treatment with the irreversible opiate antagonist beta-chlornaltrexamine. Control experiments suggested that the sigma ligands act via a neuronal mechanism to inhibit ACh release evoked by electrical stimulation or by stimulation with 5-HT. These results suggest that there are functional sigma receptors on cholinergic nerve terminals or within the myenteric plexus and that these receptors can inhibit stimulated ACh release through an opioid receptor-independent mechanism. However, sigma receptor activation in the ileum has the same effect on ACh release as activation of naloxone-sensitive opioid receptors. The LMMP may be an in vitro bioassay system for characterizing the mechanism of action of sigma receptors and for determining the biological efficacy of drugs known to bind to sigma receptors in radioligand binding assays.
西格玛受体是大脑边缘系统和感觉运动结构中特定的、高度局部化的结合位点，可与多种精神药物相互作用。这些药物包括拟精神病性苯吗喃类阿片、拟精神病性药物苯环利定及其类似物，以及众多典型和非典型抗精神病药物，如氟哌啶醇、氯丙嗪，还有新药BMY 14802和利咪唑。到目前为止，尚未明确这些结合位点的生理功能。我们合成了一些源自选择性西格玛配体N,N'-二（邻甲苯基）胍（DTG）的新型西格玛受体活性药物。发现DTG及其同系物可抑制电刺激诱发的豚鼠回肠纵肌/肠肌丛（LMMP）标本的收缩。此外，西格玛配体对5-羟色胺（5-HT）诱发的LMMP标本收缩具有非竞争性拮抗作用。发现5-HT诱发的收缩主要是由于5-HT激活5-HT3受体释放乙酰胆碱（ACh）所致。DTG同系物抑制LMMP电刺激或5-HT诱发收缩的活性与其抑制豚鼠脑匀浆中3H-DTG和（+）3H-3-PPP [3（3-羟基苯基）-N-（1-丙基）哌啶]与西格玛受体结合的效力高度相关。两种不与西格玛受体结合的DTG同系物在生物测定中也无活性。许多其他（但不是所有）西格玛受体配体在抑制LMMP电刺激诱发收缩的效力与其西格玛受体结合亲和力之间显示出高度相关性。苯吗喃类药物（+）SKF 10,047和（+）环唑辛增强了LMMP的电刺激诱发收缩。西格玛配体在阿片拮抗剂纳洛酮存在下以及在经不可逆阿片拮抗剂β-氯代去甲氯氮卓处理使阿片受体失活的标本中也抑制LMMP的收缩。对照实验表明，西格玛配体通过神经元机制抑制电刺激或5-HT刺激诱发的ACh释放。这些结果表明，胆碱能神经末梢或肠肌丛内存在功能性西格玛受体，并且这些受体可通过阿片受体非依赖性机制抑制刺激引起的ACh释放。然而，回肠中西格玛受体的激活对ACh释放的作用与纳洛酮敏感的阿片受体激活的作用相同。LMMP可能是一种体外生物测定系统，用于表征西格玛受体的作用机制以及确定在放射性配体结合测定中已知与西格玛受体结合的药物的生物学效力。
