Partial agonists intrinsic activity

Expressing the Maximal Response to a Partial Agonist Intrinsic Activity and Efficacy... 

The value for intrinsic activity ranges from 1 for a full agonist to 0 for an antagonist, and the fractional values between these extremes represent partial agonists. Intrinsic activity is a property of both the drug and the tissue in which drug effect is measured. 

DCI and DCN act as partial agonists (intrinsic activity >0) on some other fi-receptors (e.g. cardiac action, lipid mobilization). 

The term intrinsic activity (ia) was defined as a measure of the abiUty of the dmg—receptor complex to generate response. When ia = 1, a full agonist is defined when ia = 0, an antagonist is defined. Thus, values 0 < ia < 1 define partial agonists as follows, where R is the response to dmg and R is the maximum response achieved. 

Some P-adrenoceptor blockers have intrinsic sympathomimetic activity (ISA) or partial agonist activity (PAA). They activate P-adrenoceptors before blocking them. Theoretically, patients taking P-adrenoceptor blockers with ISA should not have cold extremities because the dmg produces minimal decreases in peripheral blood flow (smaller increases in resistance). In addition, these agents should produce minimal depression of heart rate and cardiac output, either at rest or during exercise (36). 

Ligands that bind to the receptor, but do not exert a maximal cellular reaction when applied at saturating concentrations are referred to as partial agonists. Their remaining activity is termed intrinsic activity ranging between 0% and 100%. 

Locomotor activity is measured in motility boxes equipped with photocells. Both horizontal and vertical movements can be registered in the modern boxes. Pretreatment with reserpine (18 h) renders the animals virtually without movement, an akinetic Parkinson-like state. It also makes postsynaptic D2 receptors supersensitive, since the receptors have been exposed to low concentrations of DA for a long period of time. The model is thus useful to reveal D2 agonists with a low degree of intrinsic efficacy and, the intrinsic efficacy of a series of partial agonists can be rated by this model. 

A true antagonist lacking intrinsic activity ( neutral antagonist ) displays equal affinity for both the active and inactive states of the receptor and does not alter basal activity of the cell. According to this model, a partial agonist shows lower selectivity for the active state and, to some extent, also binds to the receptor in its inactive state. 

The side chain and substituents on the amino group critically affect affinity for P-receptors, whereas the aromatic nucleus determines whether the compound possess intrinsic sympathomimetic activity (ISA), that is, acts as a partial agonist (p. 60) or partial antagonist. In the presence of a partial agonist (e.g., pindolol), the ability of a full agonist (e.g., isoprenaline) to elicit a maximal effect would be attenuated, because binding of the full agonist is impeded. names. 

Most full glydncB antagonists (i.e. those without intrinsic partial agonist activity) show very poor penetration to the CNS, although some agents with... 

D-cycloserine and (-l-R)-HA-966 are partial agonists at the glycincB site with different levels of intrinsic activity (Karcz-Kubicha et al. 1997). Although these systemically active partial agonists do not induce receptor desensitization they have favourable therapeutic profiles in some in vivo models (Lanthorn 1994 see Danysz and Parsons 1998). This may, in part, be due to their own intrinsic activity as agonists at the glycines site, which would serve to preserve a certain level of NMDA receptor function even at very high concentrations (Danysz and Parsons 1998). 

Kanthan R, Shuaib A (1995) Clinical evaluation of extracellular amino acids in severe head trauma by intracerebral in vivo microdialysis. J Neurol Neurosurg Psychiatry 59 326-327 Karcz-Kubicha M, Jessa M, Nazar M, et al (1997) Anxiolytic activity of glycine-B antagonists and partial agonists—no relation to intrinsic activity in the patch clamp. Neuropharmacology 36 1355-1367... 

The similarity in structure to (3-agonists is most certainly responsible for the finding that some (3-blockers activate (3-receptors that is, they have some intrinsic sympathomimetic activity. The intrinsic activity of these compounds is generally modest in comparison with an agonist, such as isoproterenol, and they are generally referred to as partial agonists (see Chapter 2). 

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