1-(3-4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine-dihydrochloride and 1-3-ditolylguanidine

SA4503, a potent sigma(1) receptor agonist, is reported as having 103-fold higher affinity for sigma(1) (IC(50) = 17.4 nM) than sigma(2) (IC(50) = 1,784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on sigma(1)/sigma(2) selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for sigma(2) sites (IC(50) = 2.11 nM) and a weaker interaction with sigma(1) sites (IC(50) = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to sigma(1) receptors in animal and human brain in vivo. We prepared SA4503 and FE-SA4503 as reference compounds for radioligand development efforts. In our hands, SA4503 is 14-fold selective for sigma(1) (K(i) = 4.6 nM) over sigma(2) (K(i) = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for sigma(1) (K(i) = 8.0 nM) over sigma(2) (K(i) = 113.2 nM) receptors. The main differences from previously reported values stem from sigma(2) affinity determinations. This protocol, displacement of [(3)H]DTG binding to sigma(2) sites using (+)-pentazocine (200 nM) to mask sigma(1) sites, was validated by the proper rank order of sigma(2) inhibitory potencies shown by a panel of additional ligands: ifenprodil > haloperidol > DTG >> (+)-pentazocine. Robust Pearson correlation (r = 1.0, P = 0.002; slope = 0.97) was observed for our pK(i) values against those from a prior study by others. The findings have bearing on structure-activity relationships for this active series, and on conclusions that might be drawn from experiments relying upon defined sigma(1)/sigma(2) binding selectivity.

Topics: Animals; Autoradiography; Binding, Competitive; Brain; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluorine Radioisotopes; Guanidines; Guinea Pigs; Haloperidol; Inhibitory Concentration 50; Ligands; Male; Narcotic Antagonists; Pentazocine; Piperazines; Protein Binding; Radioligand Assay; Radiopharmaceuticals; Receptors, sigma; Structure-Activity Relationship

We have recently developed 1-([3-O-methyl-11C]3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine ([11C]SA4503) as a selective radioligand for mapping sigma1 receptors in the brain by positron emission tomography (PET). In the present short communication we evaluated the age-related changes of the binding of this ligand to sigma1 receptors in Fisher-344 rats (1.5-, 6-, 12-, and 24-month-old) by the in vitro binding assay. We also measured the binding of [3H](+)-pentazocine to sigma1 receptors and the binding of [3H]1,3-di-O-tolylguanidine to sigma2 receptors, which are current standard methods. The specific binding of the three radioligands increased age-dependently. Both Kd and Bmax values of the 24-month-old rats for each radioligand were significantly higher than those of the young rats (1.5- and 6-month-old). The increased numbers of both sigma1 and sigma2 receptor subtypes in the aged rats compensate for the lowered affinity, and rather enhanced the radioligand-receptor binding. The results contrast strikingly with the age-dependent decrease in the dopaminergic, cholinergic and glutamatergic receptors that are reported to be correlated with the sigma receptors, and indicate that a PET study with [11C]SA4503 to evaluate the aging process in humans would be of great interest.

Topics: Aging; Animals; Brain; Carbon Radioisotopes; Cell Membrane; Dose-Response Relationship, Drug; Guanidines; In Vitro Techniques; Male; Pentazocine; Piperazines; Protein Binding; Radiopharmaceuticals; Rats; Rats, Inbred F344; Receptors, sigma; Sexual Abstinence; Sigma-1 Receptor

To clarify which subtype of sigma receptors is involved in the sigma receptor-mediated neck dystonia in rats, we examined whether 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503), a selective sigma1 receptor agonist, and 1,3-di-(2-tolyl)guanidine (DTG), a sigma1 and sigma2 receptor agonist, induce neck dystonia in rats. Microinjection of SA4503 into the red nucleus of rat brain scarcely produced neck dystonia at the concentration of 10 nmol/0.5 microl. On the contrary, DTG produced significant dystonia at a concentrations of more than 5 nmol/0.5 microl. These results indicate that the sigma2 receptor subtype, but not sigma1 receptor subtype, may play an important role in the sigma receptor-mediated neck dystonia in rats.

Topics: Animals; Dystonia; Guanidines; Male; Microinjections; Neck; Piperazines; Rats; Rats, Wistar; Receptors, sigma; Red Nucleus; Sigma-1 Receptor; Time Factors

The immobility time in the mouse forced swimming test was dose-dependently reduced by sigma 1 receptor agonists, such as 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) and (+)-pentazocine, and non-specific sigma receptor agonists, such as 1,3-di(2-tolyl)guanidine (DTG) and (+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylamin e hydrochloride (JO-1784). On the other hand, pre-treatment with N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma 1 receptor antagonist, completely antagonized the SA4503-, (+)-pentazocine- and DTG-induced reductions in immobility time. Such phenomena indicate that sigma receptor agonists alleviate behavioral despair. In addition, these antidepressive effects involve mainly the sigma 1 receptor subtype.

Topics: Animals; Anisoles; Cinnamates; Cyclopropanes; Guanidines; Male; Mice; Mice, Inbred Strains; Motor Activity; Pentazocine; Piperazines; Propylamines; Receptors, sigma; Stress, Physiological