Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

Abstract

The sigma-1 (σ₁) receptor is a 'pluripotent chaperone' protein mainly expressed at the mitochondria-endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ₁ receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ₁ receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ₁ protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ₁ receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.

Keywords: multi-target directed ligands (MTDLs); polypharmacology; sigma receptors; sigma-1 ligands; sigma-1 receptor.

Figure 1

Compound (1) and (2) and their K_i and IC₅₀ values for σ₁ receptor (σ₁ R) and human acetylcholinesterase (hAChE) [77].

Figure 2

ANAVEX 3-71, 2-73 and 1-41 structures and their K_i and IC₅₀ values for σ₁ receptor (σ₁ R) and muscarinic M1 receptor (M1 R) [82,84,85].

Figure 3

Donepezil, RS67333, and Donecopride structures and their K_i and IC₅₀ values for σ receptors (σ R), σ₁ receptor (σ₁ R), human acetylcholinesterase (hAChE) and serotoninergic 5-HT₄ receptor (5-HT₄ R) [89,90,91].

Figure 4

Compounds (3) and (4) structures and their K_i and IC₅₀ values σ₁ receptor (σ₁ R), serotoninergic 5-HT₄ receptor (5-HT₄ R) and human acetylcholinesterase (hAChE) [90].

Figure 5

Compounds (5,6) and (7) structures and pharmacological profile for σ receptor (σ₁ R and σ₂ R), human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBuChE), β-secretase 1 (BACE1), Oxygen Radical Absorbance Capacity (ORAC) and parallel artificial membrane assays (PAMPA-BBB) [99].

Figure 6

General structures of 4-chromenone and 4-quinolone classes of ligands.

Figure 7

General structure of 4-chromenone-N,N-dibenzyl-N-methylamine (DBMA) derivatives.

Figure 8

NGP-01, ANSTO-1, ANSTO-6, ANSTO-14, and ANSTO-5 structures and their K_i values for σ receptor (σ₁ R and σ₂ R) and N-methyl-D-aspartate receptor (NMDAR) [110,111,112].

Figure 9

Amantadine and memantine structures and their K_i values for σ₁ receptor (σ₁ R) and the phencyclidine binding site at the N-methyl-D-aspartate receptor (PCP) [115].

Figure 10

Pridopidine structure and its K_i values for σ (σ₁ R and σ₂ R), dopaminergic D₂ (D₂ R), alpha-2c adrenergic (α_2c R) and serotoninergic 5-HT_1a (5-HT_1a R) receptors [75].

Figure 11

Afobazole and M-11 structures and their K_i and IC₅₀ values for σ₁ receptor (σ₁ R), melatonin MT₁ and MT₃ receptors (MT₁ R and MT₃ R) and monoamine oxidase A (MAO-A), [124].

Figure 12

Haloperidol and its metabolites with K_i values for σ₁ and σ₂ receptors (σ₁ R and σ₂ R) [127,128,129].

Figure 13

Compounds (13–16) and their K_i and IC₅₀ values for σ₁ (σ₁ R), μ-opioid (MOR) and alpha-1 adrenergic (α₁AR) receptors and human ether-a-go-go-related gene channel (hERG) [139,140].

Figure 14

Compound (17) structure and its IC₅₀ values for σ₁ receptor (σ₁ R), σ₂ receptor (σ₂ R) and Na⁺ channel [144].

Figure 15

PB28 and PB221 structures and K_i values for σ₁ receptor (σ₁ R) and σ₂ receptor (σ₂ R) [153,154].

Figure 16

(R,S)-MRJF4 structure and K_i values for σ₁ receptor (σ₁ R) and σ₂ receptor (σ₂ R) [129].