1-Cyclohexylpiperazine and 3,3-Dimethylpiperidine Derivatives as Sigma-1 (sig1) and Sigma-2 (sig2) Receptor Ligands: A Review

Herein the evolution in the development of new sigma (??) receptor ligands since the middle &90s by our research group is reported. In the effort to contribute to the identification of the structural features for high-affinity ligands selective versus serotonin, dopamine and other CNS-related receptors, two general classes of (naphthalene)alkylamine compounds were prepared and explored, with the aim of addressing the affinities toward the two recognized sig receptor subtypes. The common template of these compounds was mainly an unsubstituted or methoxy-substituted naphthalene or tetralin nucleus, linked by an alkyl spacer to a substituted piperazine or piperidine ring. The design of new ligands was thought keeping in mind their possible application as PET diagnostic tools and fluorescence tools. High-affinity sig2 receptor ligands were found among N-cyclohexylpiperazine derivatives, such as 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)propyl]piperazine (3) (PB 28), when they were assayed in radioligand binding with [3H]-DTG in rat liver. Unfortunately, these ligands were all devoid of a significant selectivity relative to sig1 receptor whose binding was assayed with (+)-[3H]-pentazocine in guinea pig brain. Nevertheless, compound 3 had previously shown to be 40-fold selective with a slightly different binding method in animals' tissues. Moreover, it demonstrated 46-fold and 59-fold sig2 versus sig1 receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity sig1 receptor ligands were found, possibly due to the presence of a double N-atom and an additional reverse mode of binding. Piperidine derivatives were investigated as high-affinity and selective sig1 receptor ligands leading to some 3,3-dimethylpiperidines such as 3,3-dimethyl-1-[3-(6-methoxynaphthalen-1-yl)propyl]piperidine (69) which resulted to be highly selective relative to the sig2 receptor. For the best ligands, functional assays were conducted in order to investigate agonist/antagonist activity. The effect of chirality in the intermediate methyl-alkyl chain was explored for a class of 4-methylpiperidines linked to some (4-chlorophenoxy)alkyl moieties, and compound (-)-(S)-92 emerged as the most selective sig1 relative to sig2 receptor ligand.