Studies are in progress towards the design and synthesis of new phencyclidine (PCP)-like compounds as neuroprotective agents and as anticonvulsants. 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. PCP-like compounds have 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 found that PCP 1 binding sites exist in excitatory amino acid ion channels regulated by glutamate receptors of the N-methyl-D-aspartate (NMDA) type, as well as in the dopamine uptake complex. Our demonstration of the existence of a high affinity PCP binding site associated with the dopamine reuptake carrier raises the possibility that the therapeutic and psychotomimetic effects of PCP in humans are separable and mediated via different binding sites. Metaphit, our electrophilic affinity ligand for PCP binding sites appears to form covalent bonds with macromolecules in these binding sites. 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. We have developed new, potent and selective ligands for the sigma receptor. (+)-Pentazocine has been found to have 5,600-fold selectivity for sigma receptors over PCP receptors. Our synthesis of [3H](+)-pentazocine should greatly facilitate studies of sigma receptor sites. Further, we have synthesized 1S,2R-(-)-cis-N- methyl-N-[2-(3,4-dichlorophenyl)ethyl]-2-(l -pyrrolidinyl)cyclohexylamine. It has been found to be the most potent and selective known sigma receptor ligand, and represents the first member of a novel class of highly potent and selective sigma receptor probes which will be important for further evaluation of the structure and function of this receptor. Cannabinoid receptors were, also, studied and we have noted that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience.
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