PRE-084 hydrochloride

Ki: 2.2 and 13091 nM for σ1 and σ2 receptors respectively.

PRE-084 hydrochloride is a selective σ1 agonist with high affinity, rather than over PCP receptors (IC50 > 100000 nM) and several other receptor systems. It was reported that sigma (s) receptor ligands to alleviate learning and memory impairments on several pharmacological and pathological rodent models of amnesia, involving the s1 subtype of s receptor.

In vitro: PRE-084 had an IC50 of 44 nM in the receptor assay and an IC50 of more than 100,000 nM for PCP receptors and an IC50 higher than 1 0,000 nM in many other receptor systems. In general, hydroxy-substituted phenyl groups in these compounds like PRE-084 tended to have attenuated potency at a receptors, whereas methylphenyl and chlorophenyl substitutions enhanced potencies. Reduction of cycloalkyl ring size lowered potencies for a receptors and quatemized amine groups invariably decreased the compound’s potencies. [1]. The Sig-1R agonist PRE084 not only increases cell survival, but also counteracts the deleterious effects caused by NMHP in neuronal PC6.3 cells. Particularly, PRE084 stimulates the NF-kB pathway that is compromised by the expression of mutant huntingtin proteins, increasing the levels of cellular antioxidants. These data show that the Sig-1R agonist beneficially effects on models of HD and that compounds binding the Sig-1R may be potent targets for future drug development in HD [2].

In vivo: After exposure to CO or 14 days after intoxication with trimethyltin, the spontaneous alternation deficits was reversed significantly by the selective sigma1 ligand PRE-084 (1 mg kg-1) [3]. Administration of Pre-084 (5 mg/kg, i.p.) inhibited citric-acid-induced cough in guinea-pigs. In addition, when administered by aerosol, sigma agonist Pre-084 (1 mg/ml) inhibited cough [4].

Clinical trial: So far, no clinical study has been conducted.

References:
[1].  Su TP, Wu XZ, Cone EJ, Shukla K, Gund TM, Dodge AL, Parish DW. Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand. J Pharmacol Exp Ther. 1991 Nov;259(2):543-50.
[2].  Hyrskyluoto A, Pulli I, Trnqvist K, Ho TH, Korhonen L, Lindholm D. Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-κB pathway. Cell Death Dis. 2013 May 23; 4:e646.
[3].  Maurice T, Phan VL, Noda Y, Yamada K, Privat A, Nabeshima T. The attenuation of learning impairments induced after exposure to CO or trimethyltin in mice by sigma (sigma) receptor ligands involves both sigma1 and sigma2 sites. Br J Pharmacol. 1999 May; 127(2):335-42.
[4].  Brown C, Fezoui M, Selig WM, Schwartz CE, Ellis JL. Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol. 2004 Jan; 141(2):233-40. Epub 2003 Dec 22.

Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells.[Pubmed:25171370]

PLoS One. 2014 Aug 29;9(8):e106533.

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1beta, IL-6, TNFalpha and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.