Slow receptors

The main action of BZs occurs at the y-aminobuteric acid A (CABAa) receptors. The CABA receptors have been classified into three subtypes, CABA, CABAg, and CABA. The CABAg slow receptors are composed of seven transmembrane subunits that activate second messenger systems. CABA and CABA receptors mediate fast synaptic inhibition via transmittergated chloride ion channels (Chebib and Johnston, 1999). Each CABA and CABA receptor consists of five subunits with four transmembrane domains, which combine together to form a chloride channel (Chebib and Johnston, 1999). 

Buprenorphine is a semi-synthetic derivative of thebaine, one of the opium alkaloids. It is approximately 30 times as potent as morphine. A dose of 0.3 mg intramuscularly has a duration of analgesic action of 6-18 h. Buprenorphine is also effective sublingually. The average bio-availability by this route is about 55%, but absorption is slow and the time to achieve peak plasma concentrations is variable, with a range of 90-360 min. The onset of action is rather slow (5-15 min) after both intramuscular and intravenous administration, possibly due to slow receptor association. Buprenorphine binds to and dissociates from the p receptor very slowly, which may account for its low potential for physical abuse. It also means that buprenorphine-induced respiratory depression is difficult to reverse with naloxone, even with very high doses. Doxapram may in these circumstances be useful. Drowsiness and dizziness are the most common side effects, although they rarely... 

Side-effects Buprenorphine induces p-opioid-type side effects including respiratory depression, drowsiness, nausea and vomiting. In the clinical literature, however, there are only few cases of significant respiratory depression. Reversal of respiratory depression may need higher doses of naloxone (Gal, 1989). Buprenorphine has a limited abuse potential and withdrawal reactions, due to slow receptor dissociation, are mild and delayed. 

Weiss M, Kang W. Inotropic effect of digoxin in humans Mechanistic pharmacokinetic/pharmacodynamic model based on slow receptor binding. Pharm Res 2004 21 231-6. 

Slow receptor dissociation brings the potential for extended pharmacodynamics beyond that suggested by pharmacokinetic predictions. In monotherapy trials of CCR5 antagonists the rebound in viral load after treatment discontinuation does not appear to be immediate, but is delayed by 1-2 days for vicriviroc [145] and aplaviroc [146] and up to 5 days for maraviroc [147]. It seems likely that a combination of pharmacokinetic half-life and slow receptor offrate is required for optimal efficacy [148]. 

Receptor kinetics, in which slow receptor off-rates have been proposed to lead to enhanced duration of action in both inhaled P2AR agonists and inhaled muscarinic M3 receptor antagonists [12]. 

From the kinetic point of view the facts are different and the order is reverse, ie, the rigid highly preorganized spherands are slow, as contrasted with the flexible barely preorganized podands that are fast both in formation and decomposition of the receptor—substrate (host—guest) complex (20,21). 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

The hormonal stimulation of adenylyl cyclase is effected by a transmembrane signaling pathway consisting of three components, all membrane-associated. Binding of hormone to the external surface of a hormone receptor causes a conformational change in this transmembrane protein, which in turn stimulates a GTP-binding protein (abbreviated G protein). G proteins are heterotrimeric proteins consisting of a- (45-47 kD), /3- (35 kD), and y- (7-9 kD) subunits. The a-subunit binds GDP or GTP and has an intrinsic, slow... 

Some of the side effects due to beta blockers such as the slowing of heart rate can be counteracted by administration of drugs which antagonize the alpha adrenergic receptors. The... 

In systems where there is insufficient time for the agonist, antagonist, and receptor to equilibrate according to mass action slow-offset antagonists can produce essentially irreversible occlusion of a portion of the receptor population. This can result in insurmountable antagonism. 

Used to estimate system-independent potency of an orthosteric antagonist with a slow rate of offset. Under these conditions, a portion of the receptor population is irreversibly inactivated leading to a depression of agonist maximal response. 

Hemiequilibria, a pseudoequilibrium that can occur when a fast-acting agonist equilibrates with a receptor system where a slow acting antagonist is present. The agonist will occupy the nonantagonist bound receptors quickly and... 

GABAb receptors mediate the slow and prolonged physiological effects of the inhibitory neurotransmitter GABA. Functional GABAb receptors are comprised of two subunits, GABAbR1 and GABAbR2. Both subunits are G-protein-coupled receptors, which couple to the Gi/o family and are densely expressed at spinal nociceptive synapses. 

---