Studies are in progress towards the design and synthesis of new phencyclidine-like compounds which might exert protection against neuronal degeneration, and which might have anticonvulsant (anti-epileptic) effects. The design, synthesis, and evaluation of ligands which interact specifically with particular CNS receptors are essential for the elucidation of the function and mechanism of action of these receptors. Phencyclidine binding sites have been implicated as allosteric sites which interact with glutamate receptors of the N-methyl-D-aspartate (NMDA) type. Some phencyclidine (PCP)-like compounds have recently been reported to exert a protective effect against neuronal degeneration in ischemia models; evidence suggests they act as antagonists against the depolarizing action of NMDA in animal brain. We have now prepared a number of anticonvulsants based on the structure of PCP which have little affinity for the PCP binding site and less motor toxicity in vivo. Our affinity ligand for the PCP site, metaphit, has been used to study the function of this site and its interaction with the excitatory amino acids. Metaphit has also been shown to interact with the dopamine uptake complex in the mouse striatum labeled by [3H]mazindol and was found to produce a long term blockade of [3H]mazindol binding. Several lines of evidence indicate that the blockade occurs through covalent bond formation with the isothiocyanate function present in metaphit. We have now tritiated metaphit to high specific activity and the labeled material promises to be a valuable tool for further study of the NMDA receptor-coupled binding site and the dopamine uptake complex. A new and more potent affinity ligand for the PCP binding site, etoxadrol isothiocyanate, has been designed and synthesized. We have synthesized a fluorinated derivative of TCP (the 2-thienyl analog of PCP) as a potential agent for imaging NMDA coupled PCP binding sites by positron emission tomography (PET) scanning and shown that it binds substantially better than PCP to this site. This drug has been tritiated to high specific activity for in vivo autoradiographic studies and an efficient radiochemical synthesis of the [18F] labeled material has been developed. Sigma receptors are non-dopaminergic, non-opioid receptors which bind antipsychotic drugs and have been implicated in neural regulation of motor behavior and modulation of transmitter release upon electrical stimulation of smooth muscle preparations. New, potent and selective ligands for the sigma receptor were also developed.
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