Intrinsic efficacy

Different drugs have different inherent capacities to induce response (intrinsic efficacy). Thus, equal cellular responses can be achieved by different fractional receptor occupancies of these drugs. 

FIGURE 3.5 Major components of classical receptor theory. Stimulus is the product of intrinsic efficacy (s), receptor number [R], and fractional occupancy as given by the Langmuir adsorption isotherm. A stimulus-response transduction function f translates this stimulus into tissue response. The curves defining receptor occupancy and response are translocated from each other by the stimulus-response function and intrinsic efficacy. 

FIGURE 9.15 In vivo effec ts o f P-adreno cep tor partial agonis ts o f differing in trinsic efficacy. Changes in heart rate (increases in beats/min) shown in anesthetized cats. Chloralose/pento barbital anesthesia (filled circles) yield low basal heart rates, while urethane/pen to barbital anaesthesia (open circles) yields high basal heart rates. Responses to (in order of descending relative intrinsic efficacy) (a) pirbuterol, (b) prenalterol, and (c) pindolol. Redrawn from [50],... 

EPMRs depend only on agonist affinity and intrinsic efficacy. 

Intercellular adhesion molecule-1, 128 Interfacial inhibition, 159 Intrinsic activity, 44-46 Intrinsic efficacy, 9, 45, 115 Inverse agonism, 49, 108 Inverse agonists... 

Fig. 1). If an agonist produces a submaximal system response it is called a partial agonist (Fig. 1). While the potency of an agonist is quantified by the location parameter of the dose-response curve (EC50), a reflection of (but not a direct measure of) the intrinsic efficacy of an agonist is given by its maximal response. 

Efficacy is a parameter which describes the strength of a single drug-receptor complex in evoking a response from the cell or tissue. The intrinsic efficacy of a drag is a proportionality constant that defines the power of the drug to induce a response. 

In humans as well as in other but not all mammalian species, kininogens are modified by posttranslational hydroxylation of a single proline residue of their kinin sequence, i.e. position 3 in bradykinin or position 4 in kallidin. Hydroxylation appears not to affect the specificity, affinity or intrinsic efficacy of the kinins. 

Intracellular Transport Intrathecal Application Intrathecal Space Intrinsic Efficacy Intron... 

Khan MZ, Brandrmarti R, Patel JP, Huynh N, Wang J, Huang Z, Fatatis A, Meucd O (2004) Apoptotic and antiapoptotic effects of CXCR4 is it a matter of intrinsic efficacy Implications for HIV neuropathogenesis. AIDS Res Hum Retroviruses 20 1063-1071... 

Here, [R]T is the total concentration of receptors, and e (epsilon) is the intrinsic efficacy (not to be confused with intrinsic activity) e can be regarded as a measure of the contribution of individual receptors to the overall efficacy. 

Suppose that L combines only with the inactive, R, form. Then the presence of L, by promoting the formation of LR at the expense of the other species, will reduce the proportion of receptors in the active, R, state. L is said to be an inverse agonist or negative antagonist and to possess negative efficacy. If, in contrast, L combines with the R form alone, it will act as a conventional or positive agonist of very high intrinsic efficacy. 

Thus, the intrinsic efficacy of an agonist is influenced by both KARG and [G]T as well as, of course, by E. 

This term has increasingly come to be employed (as here) in a rather different sense from that introduced by R. F. Furchgott (Section 1.4.2). With this newer usage, intrinsic efficacy indicates the maximum receptor activation (often expressed as the fraction of receptors in the active state) that can be achieved by an agonist acting through a mechanism that can be formulated and studied at the molecular level, as in the present example. The intention of this redefinition is to focus on the receptor itself and its immediate transduction mechanism (e.g., G-protein activation), rather than on the cellular events that follow. 

An alternative to neuroleptics would be to develop partial DA receptor agonists. Such agonists will preferentially stimulate the sensitive D2 autoreceptors and block the less sensitive postsynaptic D2 receptors. Still, such compounds should have a some degree of intrinsic efficacy for the postsynaptic DA receptors in order not to be cataleptogenic [13]. Neuroleptic-induced catalepsy in rats is considered to be predictive for the precipitation of EPS in the clinic. There are now quite a few partial D2 receptor agonists under clinical evaluation (see below), and the near future will show whether this approach offers some advantage over the classical neuroleptics, which all potently block postsynaptic DA receptors. 

The DA receptor regulating prolactin release in the pituitary is of the D2 " type [50]. This view is substantiated by the studies of Carlsson and coworkers, who reported that prolactin release response is different in male and female rats given partial DA agonists of different intrinsic efficacy [13]. In these studies, endogenous DA was depleated and prolactin levels were... 

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. 

Potency is the dose of drug required to produce a specific effect of given intensity as compared to a standard reference. Potency is a comparative rather than an absolute expression of drug activity. Drug potency depends on both affinity and efficacy. Thus, two agonists can be equipotent, but have different intrinsic efficacies with compensating differences in affinity (IUPAC). 

The structural manipulation at different positions of adenosine provided a wide number of ligands at the A3 AR exerting different levels of potency, selectivity, and intrinsic efficacy. The exact combination of modifications showed to affect the balance between full agonism, partial agonism and antagonism (Joshi and Jacobson 2005). 

It has been demonstrated that the introduction of a benzyl or a 3-iodobenzyl moiety at the N6- position and a Cl substituent at the 2-position of adenosine synergistically contribute to reduce the intrinsic efficacy of the corresponding nucleoside derivatives. 

Lohse, M. J., Vilardaga, J. P., and Bunemann, M. (2003). Direct optical recording of intrinsic efficacy at a G protein-coupled receptor. Life Sci. 74, 397-404. 

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