Sigma receptor modulators: a patent review

Abstract

In recent years, considerable progress in the knowledge of the biology and pharmacology of sigma receptors has encouraged research on the potential benefits of sigma modulators in a wide range of pathologies. So far, only few potent agonists and antagonists of sigma receptors are in clinical trial for acute and chronic neurodegenerative diseases (SA4503 and ANAVEX 2-73) or neuropathic pain (E-52862).

A review on Alzheimer's disease pathophysiology and its management: an update

“…357 AF150(S) and AF267B have also shown promising results in the 358 preclinical setup [59]. ANAVEX 2-73 is a mixed muscarinic/s1 359 agonist and is currently in phase I/IIa trials [60]. A few recent 360 studies highlight the use of the metabolite of nicotine ''cotinine'' in 361 cognitive enhancing potential this compound is a positive 362 allosteric modulator of a7 nicotinic AChRs [61].…”

The involvement of sigma1 receptors in donepezil-induced rescue of hippocampal LTP impaired by beta-amyloid peptide

“…Sig1-Rs regulate a variety of cellular functions, such as Ca 2+ signaling, ion channel firing, protein kinase translocation/activation, neurotransmitter release, lipid metabolisms/transports, trophic factor signaling, cellular differentiation, cellular protection against beta-amyloid-induced neurotoxicity and others (for a review, see Kourrich et al, 2012;Hayashi and Su, 2010). These receptors have been shown to be involved in several central nervous system (CNS) disorders, including mood disorders (depression and anxiety), psychosis, schizophrenia, movement disorders (i.e., Parkinson's disease) and memory deficits (i.e., AD) (for a review, see Collina et al, 2013). Sig1-R agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others, CNS administration of ␤-amyloid peptides (A␤) (for a review, see van Waarde et al, 2011).…”

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

“…The sigma-1 receptor is a ligand-regulated molecular chaperone that modulates several receptors and ion channels123 and is involved in a variety of neurological disorders456. Consequently, in recent years this pharmacological target has been the subject of intense basic research and drug development of both σ 1 agonists and antagonists57.…”

“…Consequently, in recent years this pharmacological target has been the subject of intense basic research and drug development of both σ 1 agonists and antagonists57. Selective σ 1 ligands are available to study σ 1 receptor function, including the prototypical σ 1 agonists (+)-pentazocine and PRE-084, and the σ 1 antagonists BD-1063, BD-1047 and S1RA28.…”

“…Whether σ 1 agonists are pronociceptive is not a trivial question, since as noted above, several drugs that are marketed for clinical use, although not selective for σ 1 receptors, are able to bind this receptor and thereby act as nonselective σ 1 agonists. Moreover, some selective σ 1 receptor agonists are currently being tested in clinical trials5.…”