Central Nervous System Agents in Medicinal Chemistry

(Formerly Current Medicinal Chemistry - Central Nervous System Agents)


1-Cyclohexylpiperazine and 3,3-Dimethylpiperidine Derivatives as Sigma-1 (σ1) and Sigma-2 (σ2) Receptor Ligands: A Review

Author(s): Francesco Berardi, Carmen Abate, Savina Ferorelli, Nicola Antonio Colabufo, Roberto Perrone.


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 σ 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 σ2 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 σ1 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 σ2 versus σ1 receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity σ1 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 σ1 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 σ2 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 σ1 relative to σ2 receptor ligand.

Keywords: PB28, Cyclohexylpiperazines, 3,3-Dimethylpiperidines, Sigma () receptors, Sigma-1 (1) receptors, Sigma-2 (2) receptors, Structure-Affinity Relationship (SAfiR), Sigma (σ) receptors, Sigma-1 (σ1) receptors, Sigma-2 (σ2) receptors

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Article Details

Year: 2009
Page: [205 - 219]
Pages: 15
DOI: 10.2174/1871524910909030205
Price: $58