Naloxone selectivity

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

Selective antagonists (naloxone) CTAP Naltrindole Nor-binaltorphimine J-113 397... 

There are now selective antagonists for all three opiate receptors (see Table 21.2) but with the exception of naloxone they are experimental tools for probing the functional roles of the opiate receptors. Naloxone is a potent competitive antagonist at all three receptors with highest affinity for the mu receptor. It will rapidly reverse all opiate... 

Delta receptors are relatively selective for two related penta-peptides, methionine enkephalin and leucine enkephalin (met- and leu-enkephalin), which were isolated from porcine brain (Hughes 1975). Both met- and leu-enkephalin inhibit electrically induced contractions of guinea pig ileum, an effect that mimics those effects seen with opioid drugs, and is naloxone reversible. The enkephalins are processed posttranslational ly from proenkephalin, and secreted from central and peripheral neurons and endocrine cells in the adrenal medulla. 

Opioids create their effects by acting at opioid receptors (table 8.3). These are, namely, p, k, and 5. Each is further divided into subtypes, which are differentially distributed throughout the nervous system pi, pi, 51, 52, k1, and k3. A k2 receptor was defined pharmacologically, but no one to date has cloned a receptor that resembles it (Zukin et al. 1998). Selective agonists have been developed for the receptor subtypes (see table 8.3). Naloxone is a general antagonist for all classical opioid receptors. All opioid receptors create cellular effects through G-protein-... 

For the treatment of poisoning, a selective antidote (which antagonises the action) may be given e.g., nalorphine and naloxone in case of morphine poisoning, atropine in case of anticholinergic drugs, dimercaprol in mercury and penicillamine in lead poisoning, etc. 

Olofson, R.A., Schnur, R.C., Bunes, L., Pepe, J.P. Selective N-dealkylation of tertiary amines with vinyl chloroformate - an improved synthesis of naloxone, Tetrahedron Lett. 1977, 1567-1571. 

Those related to the respiratory apparatus are of special interest DPDPE causes a dose dependent increase in foetal respiratory activity which was blocked by administration of naloxone (Cheng et al., 1992). These stimulatory effects of selective 5 agonists may be of clinical value in treating respiratory disorders such as apnoea. 

Low-dose naloxone (0.04 mg) has an increasing role in the treatment of adverse effects that are commonly associated with the use of intravenous or epidural opioids. Careful titration of the naloxone dosage can often eliminate the itching, nausea, and vomiting while sparing the analgesia. Oral naloxone, and more recently developed nonabsorbable analogs of naloxone, have been shown to be efficacious in the treatment of opioid-induced ileus or constipation. The principal mechanism behind this selective therapeutic effect is believed to be local inhibition of receptors in the gut with minimal systemic absorption. 

An examination of the structure-activity relationship (SAR) of a series of enkephalin analogues and morphine derivatives in competing with the binding of radioisotope labeled DADLE and FK 33-824 or opiates revealed that DADLE binds to an opioid receptor selective to Leu-enkephalin and its analogues. In contrast, FK 33-824, morphine, or naloxone binds to opioid receptors with selectivity in favor of morphine and derivatives simi-... 

Opioids are known to have complex effects on body temperature in animals [46]. Depending on the receptor selectivity of an opioid, but also on several other factors such as dose, route of administration, the gender of the animal, or handling procedures, it may produce either a rise or a fall in body temperature. Biphalin, after peripheral administration in mice, produced a dose-dependent (in the range 0.1-20 mg/kg) hypothermic effect that was naloxone reversible [47]. 

---