5- Receptor affinity

The principal organs involved in the peripheral clearance of hGH from the plasma are the kidney and fiver. hGH is cleared via glomerular filtration at the kidney and by a receptor-mediated mechanism at the fiver (58,59). In animal models, derivatives of hGH such as the 20,000 mol wt variant, oligomeric forms, and hGH complexed with GH-binding protein have been shown to be cleared from the semm at significandy lower rates than 22,000 mol wt hGH (60—62). The prolonged plasma half-life of these derivatives probably reflects a combination of decreased receptor affinity and size constraints on glomerular filtration. 

H-Tyr-cyclo[-D-Om-Phe-Asp]-NH2 and its derivatives (87), which have been used to characterize the importance of the arrangement of the Tyr and Phe aromatic rings to. -receptor affinity. 

H-Tyr-D-Ala-Pile-Asp-Val-Val-Gly-NH2 (D-Ala -deltorpliiu I) and H-Tyr-D-Ala-Plie-Glu-Val-Val-Gly-NH2 (D-Ala -deltorpliiu II) display greater 5-selectivity than DPDPE owiag to their higher 5-receptor affinity (96). These compounds both contain the same N-terminal tripeptide sequence as the. -selective dermorphins, which underscores the importance of the C-terminal tetrapeptide sequence in conferring 5-selectivity. 

Pharmacogenetics the responses to dmgs may be significantiy different according to heritable factors that can modulate pharmacodynamic or pharmacogenetic factors (118). Atypical cholinesterase occurs in about 1 in 2000 Caucasians and is associated with a markedly reduced sensitivity to hydrolysis of the muscle-relaxant cholinesterase. Similarly, the reduced sensitivity to the anticoagulant warfarin is associated with a reduced receptor affinity. 

Correlation between clinical effectiveness and receptor affinities, however, can be seen with other receptors in addition to the dopamine D2 receptor. These include other dopaminergic receptors, as well as noradrenergic and serotonergic receptors. For example, most antipsychotics also have high affinity for a -adrenoceptors and 5-HT2 receptors (225). Some antipsychotics have been shown to be selective for the adrenoceptor versus the a -adrenoceptor, for example, spiperone [749-02-0] (226) and risperidone (61) (221]... 

To solubilized lat hepatic nuclear protein receptor Affinities and potencies are relative to L-T taken as 1 (6). 

Resultant analysis, this procedure, developed by James Black and colleagues (Br. J. Pharmacol. 84,561-571, 1985), allows measurement of the receptor affinity of a competitive antagonist, which has secondary properties that obscure the receptor antagonism see Chapter 6.6 for further discussion. 

Rational design, 148-149, 152 Real-time assays, 83, 88 Receptor(s). See also Drug receptors affinity for, 6, 63 allosteric model of, 143 Clark s work, 3 classical model of, 44-45 concept of, 2-4 conformations, 13-14, 13 Of conservation equation for, 76 constitutive activity of, 49-51 coupling of, 27 definition of, 2 desensitization of, 34 efficacy for, 6... 

Adapalene (Table 1), a new highly stable naphtoic acid arotinoid with lipophilic properties, does not bind to CRABP, although it enhances its synthesis, and its rank-order of retinoid receptor affinity apears to be RAR(3 > RARy > > RARa. 

Thus three lines of evidence define the rapidly dissociating receptor as the LR complex. Conditions known to uncouple R from G--first, guanine nucleotide and second, pertussis toxin—produce LR third, reconstitution of G protein restores receptor affinity, sensitivity to guanine nucleotide, and effector activation. In this sense, the ligand and binding behavior of this system is analogous to that of the beta-adrenergic receptor, where the LR and LRG complexes have already been studied with purified proteins and reconstituted membrane preparations (2,i0). 

Desensitization is accompanied by increased agonist-receptor affinity and stimulation of channel activity at low concentrations. 

Inhibition of EGF binding by palytoxin could be due to a decrease in receptor affinity, as in the case of TPA-type tumor promoters, and/or a decrease in receptor number. In Swiss 3T3 cells there are two classes of EGF receptors. The dissociation constants for the two EGF receptor classes were determined to be approximately 2 X 10 M and 2 x 10" M, corresponding to approximately 1 x 10 and 1 X 10 receptor molecules per cell, respectively (33). Scatchard analysis revealed that treatment of Swiss 3T3 cells with palytoxin, like PDBu, caused an apparent loss in high-affinity binding (Figure 2). However, in contrast to PDBu, palytoxin also caused a significant (approximately 50%) loss of low affinity EGF binding. 

MMP Processing of CXCL12 is Associated with a Shift of Receptor Affinity from CXCR4 to CXCR3... 

Some propeptides lead to the production of different, in terms of receptor affinities, peptides (substance P and neurokinin A act on neurokinin 1 and 2 receptors, respectively). 

Mokrosz JL et al. (1995) Structure-activity relationship studies of CNS agents, XIX Quantitative analysis of the alkyl chain effects on the 5-HTlA and 5-HT2 receptor affinities of 4-alkyl-1-arylpiperazines and their analogs. Arch Pharm (Weinheim) 328(2) 143-148... 

In the following example from the literature [39], the correlahon with lipophilicity is studied for 47 compounds in two series which have been designed for dopamine D2 receptor affinity. As seen in Fig. 17.1, there is no clear relahon between D2 activity and lipophilicity (r=0.11). 

Glennon, R.A. Liebowitz, S.M. and Anderson, G.M. Serotonin receptor affinities of psychoactive phenalkylamine analogues. J Med Chem 23 294-299, 1980. 

A range of different functional groups has been introduced into the V-position of the C3 side chain, as shown in Table 6.10. A number of different functionalities were shown to be tolerated in this position, with lipophilic groups such as methyl and dithiolane being preferred over polar groups such as ketones and alcohols. Ketone (118) had similar CBi receptor affinity to the unfunctionalised -heptyl compound (84), while alcohol (120) had lower affinity. The phenyl ketone (119) had lower CBi receptor affinity than the simple benzyl-substituted compound (116), but higher CB2 affinity, with about 12-fold selectivity for CB2 over CBi. 

In general, modification or deletion of the Cl phenolic hydroxyl group results in significantly reduced CBi receptor affinity [93]. A number of 1-deoxy and 1-alkoxy A -THC analogues have been shown to be selective ligands for the CB2 receptor (see below). 

Cannabidiol has low affinity for CBi and CB2 receptors and is not psychoactive, but has nevertheless shown a number of pharmacological activities of its own including anti-inflammatory and neuroprotective effects. Some side chain-modified cannabidiol derivatives have also been evaluated for can-nabinoid receptor affinity and these are shown in Table 6.15. 

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