Ligands for the sigma receptor system were studied. 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. A considerable variety of compounds, of very different structural types, can interact with the known sigma receptor subtypes. Various disubstituted piperazines have been synthesized and found to have good affinity for the sigma-1 receptor. However, zipeprol, which is also a disubstituted piperazine (4-(2-methoxy-2-phenylethyl)- alpha-methoyphenylmethyl-1-piperazineethanol), is a potent sigma-2 receptor agonist and is somewhat selective for that receptor subtype (sigma-1/sigma-2 ratio about 7). Zipeprol has been found to have a novel spectrum of action involving both opioid and non-opioid effects, as well a its effects due to its interaction with the sigma receptor. In our continuing study of the opioid receptor system, we have examined conformationally fixed derivatives of the potent class of narcotic agonists, 5-(3-hydroxyphenyl)morphans. This class of opioid is known to exhibit potent antinociceptive activity as well as narcotic agonist- antagonist activity, depending on the particular optical isomer. The parent compounds have a rigid 2-azabicyclo[3.3.1] nonane ring system with a freely rotating phenyl group attached at the 5-position. In order to gain insight into the topological features of opioid receptor binding sites we have undertaken a study aimed at determining the optimum torsion angle between the phenyl ring and piperidine ring for binding to the mu opioid receptor. There are a total of 8 isomers possible in the class of oxide-bridged molecules, of which six have been successfully synthesized in our laboratory, thus far. The synthesis of a seventh is now being approached through a key intermediate in the postulated synthesis scheme. The synthesis of chiral GBR 12909 analogs with trans-25-dimethyl substitution on the central piperazine ring in our laboratory has produced high affinity, slowly dissociating, low intrinsic activity cocaine receptor agonists which may prove useful as treatment agents A new methodology has been devised towards the synthesis of a large variety of chiral di-and mono-substituted GBR analogs. This new enantioselective synthetic methodology involves the use of enantiomerically pure amino acids.
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