Sigma subtypes

In 1976 Martin proposed the theory that there are three subtypes of opioid receptor on the basis of behavioural studies using a chronic spinal dog model which revealed that the opioids morphine (mu) (1), ketazocine (kappa) (2) and A-allylnormetazocine (SKF 10047) (4) (sigma) had different effects on respiration, heart rate and locomotor activity [13]. Furthermore, these ligands were unable to replace each other to prevent withdrawal symptoms in dogs that had been chronically treated with one of the compounds. 

Remoxipride is a selective D2 antagonist with higher affinity for the D2S subtype of receptors. It has no affinity for 5-HT, adrenergic, muscarinic or histamine receptors but, unlike the other atypical neuroleptics, does bind to sigma receptors (see p. 453 for possible importance of sigma receptors). 

As part of our program to investigate the role of sigma-1 and -2 receptor subtypes, we focused our attention on the high affinity ethylenediamine sigma ligand 3 (Figure 1) and used it as a template [5]. 

Our interest in the development of sigma-2 selective ligands was spurred by evidence that this subtype may be responsible for the motor effects of sigma ligands (Bowen WD et al., personal communication). This is reinforced by the observation that DTG, which binds with lower affinity to sigma-1 receptors than (+)-pentazocine, is nonetheless more effective at causing motor disturbances in rats. 

Bowen, W.D., Bertha, C.M., Vilner, B.J., Rice, K.C., 1995a. CB-64D and CB-184 ligands with high sigma-2 receptor affinity and subtype selectivity. Eur. J. Pharmacol. 278, 257-260. 

Itzhak, Y., Stein, I., Zhang, S.H., Kassim, C.O., Cristante, D., 1991. Binding of sigma-ligands to C57BL/6 mouse brain membranes effects of monoamine oxidase inhibitors and subcellular distribution studies suggest the existence of sigma-receptor subtypes. J. Pharmacol. Exp. Ther. 257, 141-148. 

Monnet, F.P., de Costa, B.R., Bowen, W.D., 1996. Differentiation of sigma ligand-activated receptor subtypes that modulate NMDA-evoked [ H]-noradrenaline release in rat hippocampal slices. Br. J, Pharmacol. 

Monnet, F.P., Debonnel, G., Fournier, A. deMontigny, C. (1992b) Neuropeptide Y potentiates the TV-methyl-D-aspartate response in the CA3 dorsal hippocampus, involvement of a subtype of sigma receptor. J. Pharmacol. Exp. Ther. 263, 1219-1225. 

Four principal opioid receptor subtypes, designated as mu, kappa, delta, and sigma, have been characterized [1,2]. A newer receptor classification system utilizes labels OPRj, OPR and OPR, which correspond to mu, kappa, and delta receptors respectively [1,3,8]. Mu receptors (OPR ) mediate supraspinal analgesia, as well as respiratory depression, nausea and vomiting, miosis and bowel hypomotil-ity. Mu receptors also mediate euphoria and physical and psychological dependence, and are responsible for the increased release of prolactin and growth hormone [1,2]. 

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