(-)-4-[11C]Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine

Excerpt

Opioids such as morphine are commonly used analgesics in clinical practice. Three opioid receptors (mu, µ; delta, δ; and kappa, κ) that mediate opioid effects have been identified by molecular cloning: δ (enkephalin-preferring), κ (dynorphin-preferring), and µ (ß-endorphin-preferring) (1). Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies (2, 3). Their specificity and ubiquitous location are present in both the central and peripheral nervous system. The opioid receptors (G-protein coupled, resulting in decrease in adenylyl cyclase activity) play an important role in the regulation of analgesia, shock, appetite, thermoregulation, cardiovascular, mental and endocrine function (2-5). Although µ opioid receptors are the major receptor to mediate the analgesic effects of opioids, δ and κ receptors are also important in antinociception. Opioids have been found to protect cells from ischemia injury in the heart and brain via the δ receptors. On the other hand, κ antagonist prevents neurodegeneration.

In humans, the κ opioid receptors (κ₁ and κ₂ ) are the most abundant brain opioid receptors and are widely distributed in deeper layers of the neocortex (particularly temporal, parietal, and frontal cortices), striatum, and thalamus, with lower levels in the amygdala, hippocampus, occipital cortex, and cerebellum (6, 7). The κ opioid receptors have been implicated in several clinical brain disorders, including substance abuse (8), epilepsy (9), Tourette’s syndrome (10), and Alzheimer’s disease (11).

(±)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a novel, highly potent, and selective κ opioid receptors agonist (12). The (–)-isomer, (–)-4-methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine, also known as GR103545, is the more potent optical isomer of GR89696 (IC₅₀, 0.018 nM versus 6.0 nM). GR89696 is centrally penetrating, with a log P value of 3.14, and has potent antinociceptive, sedative, and diuretic effects. K_i values for GR89696 κ₁- and κ₂-receptor binding are in the low nanomolar or subnanomolar range. GR89,696 is an agonist for κ₂ opioid receptors and an antagonist at κ₁ receptors in the guinea pig hippocampus (13). [¹¹C]GR103545 is being developed as a PET agent for the non-invasive study of the κ receptors in the brain.