Among the CNS-active compounds which we have studied are ligands which interact with the PCP (phencyclidine) site, and those which interact with the sigma receptor. Our new, very high affinity and site selective sigma ligands will help elucidate the function of that receptor system. Ligands for the PCP site: Studies are in progress towards the design and synthesis of new PCP-like compounds as neuroprotective agents and as anticonvulsants. 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 N-methyl-D-aspartate (NMDA) in animal brain. PCP binding sites exist in excitatory amino acid controlled ion channels regulated by glutamate receptors of the NMDA type, as well as in the dopamine uptake complex. Our initial electrophilic affinity ligand, metaphit, was an essential tool for the determination of dopaminergic neurotransmission in rat striatal slices and the involvement of the dopamine transporter and voltage-dependent sodium channel. Computer-assisted molecular modeling (CAMM) was used to examine the relative activities of isomeric methyl-substituted PCP isomers, one of which we determined to be among the most potent known PCP-like compounds. The CAMM study was based on a least squares fit to the pharmacophore and the calculation of the stability of the minimum energy conformer with the phenyl axial orientation. Future determination of the spatial area required by the macromolecule involved in binding should enable more accurate prediction of the activity of ligands. Ligands for the sigma receptor: 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 identified a novel class of high-affinity sigma receptor ligands, the enantiomeric N-substituted cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1- pyrrolidinyl)cyclohexylamines. The most potent, site selective, sigma ligand found in this group was the 1R,2S-(-)-unsubstituted derivative (Ki=0.49 nM). Related compounds constitute a new class of superpotent signma ligands. Optically pure [3H](+)-cis-N-(2-(4-azidophenyl)ethyl)-2'- hydroxy-2,6-dimethyl-6,7-benzomorphan was synthesized and characterized as a high affinity and highly selective benzomorphan-based photoaffinity label for sigma receptors.
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