Alazocine shows stereoselectivity in its pharmacodynamics. The -enantiomer is a non-selective and high-affinity ligand of the μ-, κ-, and δ-opioid receptors with very low affinity for the sigma σ1 receptor. It acts as a moderate-efficacy partial agonist of the κ-opioid receptor and as an antagonist of the μ-opioid receptor. It is also an agonist of the δ-opioid receptor with far lower potency. Conversely, the -stereoisomer has little affinity for the opioid receptors and instead is a selective and high-affinity agonist of the σ1 receptor. However, the -enantiomer also shows moderate affinity for the dizocilpine or phencyclidine site of the NMDA receptor and, hence, is an uncompetitiveNMDA receptor antagonist as well at higher concentrations. As such, -alazocine is only modestly selective as a ligand of the σ1 receptor. Both enantiomers of alazocine have very low affinity for the sigma σ2 receptor - and. As such, due to its high affinity for the σ1 receptor, -alazocine can be used to distinguish between the two sigma receptor subtypes in scientific research, for instance in radioligand binding assays. Taken together, -alazocine is a selective partial agonist of the κ-opioid receptor, antagonist of the μ-opioid receptor, and to a far lesser extent agonist of the δ-opioid receptor with very low affinity for the sigma receptors, while -alazocine is a selective agonist of the sigma σ1 receptor and to a lesser extent antagonist of the NMDA receptor with low affinity for the opioid and sigma σ2 receptors.
History
Alazocine was one of the early members of the benzomorphan family of opioid analgesics to be investigated. It was first described in the scientific literature in 1961. Its development resulted from nalorphine, a potent analgesic and opioid antagonist with similar pharmacology which had been introduced in the mid-1950s. Alazocine was found to produce strong psychotomimetic effects in humans, and it was not further developed for clinical use. Subsequently, other benzomorphans, such as pentazocine, cyclazocine, and phenazocine, were developed, and some have been marketed for use as analgesics. The sigma σ1 receptor was named in 1976 and -alazocine was described as its prototypical ligand. The receptor was initially thought to be an opioid receptor, and then was confused with the NMDA receptor for a time, but was ultimately distinguished from them both. The psychotomimetic effects of alazocine and the other benzomorphans were initially attributed incorrectly to agonism of the σ1 receptor; subsequent research established that the effects are in fact caused by agonism of the κ-opioid receptor and/or antagonism of the NMDA receptor. The sigma σ2 receptor was discovered and named in 1990, and was identified in part due to the dramatically reduced affinity of alazocine for the receptor relative to the σ1 receptor.
