SELECTIVE SIGMA LIGANDS: DESIGN SYNTHESIS & EVALUATION

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Relatively little is known about sigma pharmacology except that agents with appreciable affinity for sigma sites either produce schizophrenic- like psychotic symptoms or alleviate/attenuate such effects. On the basis of these findings, it has been suggested that sigma-selective agents (antagonists) might represent a new mechanistic class of neuroleptic agents that lack many of the undesirable side effects associated with the classical neuroleptics. Sigma-opiates, various classical neuroleptics such as haloperidol, and certain other agents bind at sigma sites, but lack high affinity and/or selectivity. To date, no high-affinity sigma-selective agents have been reported. In fact, little has been published in the way of structure-activity relationships (SAR) for sigma agents, and structural requirements for sigma agonists and antagonists are unknown. Furthermore, the one functional model of sigma activation appears to suffer from a lack of high affinity sigma-selective agonists. Indeed, current studies are seemingly dictated by the non- selective agents that are presently available. Thus, there is a need both for the development of high-affinity sigma-selective agonists and antagonists. The proposed investigation, whose goals are to develop sigma-selective agents and to determine how various structural features affect affinity, intrinsic activity, and selectivity, represents the first systematic study involving the rational design of such agents. We have identified what we believe is the primary pharmacophore of the sigma-opiates. Structural modification of this pharmacophore (i.e. PAP) has already resulted in several agents that bind at sigma sites with very high affinity. Furthermore, unlike sigma-opiates, PAP analogs display little to no affinity for PCP binding sites, and unlike haloperidol, they display low affinity for dopamine sites. Modeling studies have revealed other types of compounds that are anticipated to bind at sigma sites with similar or an even higher affinity than the PAP analogs. We have designed, using an extrathermodynamic approach, new agents that we propose to synthesize and evaluate using, initially, in vitro radioligand binding and drug discrimination techniques (with rats as subjects). The binding studies will provide a measure of sigma affinity (agonist vs antagonist action). Subsequent drug discrimination studies will employ one of our novel, more selective sigma agonists as a training drug. Overall, then, our investigations will permit the determination of what molecular features are important for affinity, intrinsic activity, and selectivity. In addition, on the basis of our preliminary results, we also propose to prepare new radioligands that should be useful for the further characterization of sigma receptor/binding sites.