Receptor subtype selectivity

Kaumann, A. J., and Marano, M. (1982). On equilibrium dissociation constants for complexes of drag receptor subtypes Selective and nonselective interactions of partial agonists with two P-adrenoceptor subtypes mediating positive chronotropic effects of (-) isoprenaline in kitten atria. Nannyn Schmiedebeberg s Arch. Pharmacol. 219 216—221. 

Future generations of such receptor subtype-selective retinoids or also retinobenzoic acids [3] may provide clinicians with more specific and less toxic diugs for dermatologic therapy. 

Receptor subtype selective CB2 agonists are seen as potential candidates for the treatment of a variety of diseases, including pain-related indications. The promise of useful therapeutic effects without unwanted CNS side effects makes the development of CB2 selective compounds a particularly attractive... 

Rivkees SA, Lasbury ME, Barbahalya H. Identification of domains of the human Ai adenosine receptor that are important for binding receptor subtype selective ligands using chimeric Ai/A2 adenosine receptors. J Biol Chem 1995 270 20485-20490. 

Despite the discovery of ERcx selective SERMs and their subsequent use as chemical tools to evaluate the pharmacological significance of this receptor sub-type, the respective roles that ERcx and ER(3 play in regulating tissue selectivity is not yet clear. As a result, the identification of non-receptor subtype selective SERMs remains of considerable interest. Along these lines, isochroman 26 and... 

An increase in the elimination half-life in rats was achieved by blocking the benzylic position of the propionic acid chain by introduction of a cyclopropane ring 22 (%F = 88, Vdss = 1 L/kg, f1/2 = 6.3 h) however, in the case of 22, this led to a reduction in the receptor subtype selectivity (EC50 on SI Pi/1,5 = 0.21,123 and 5.1 nM, respectively). Similarly, blocking the benzylic position by cyclizing onto the phenyl ring to form indanylacetic acid 23 resulted in an improved elimination of half-life (%F — 71, Vdss = 0.4L/kg, f1/2 = 6.7h). Acid 23 showed a similar pharmacokinetic profile in the dog and showed efficacy in the rat skin transplantation model when combined with sub-therapeutic doses of CsA. Compound 23 has been reported to be efficacious in the rat EAE model when dosed therapeutically or prophylactically [94—96]. 

Hwa, J., Graham, R.M. and Perez, D.M. (1995) Identification of critical determinants of alpha 1-adrenergic receptor subtype selective agonist binding. The Journal of Biological Chemistry, 270, 23189-23195. 

The majority of studies aimed at preparing kappa-selective opioids have used U-50488 (5) as the chemical lead and, as the above discussion shows, this has proved to be a highly productive approach. However, as was pointed out above, there are other structures [EKC (3), tifluadom (6) and the peptide dynorphin (7)] which have been reported to bind to the kappa receptor, albeit with poor opioid receptor subtype selectivity. Some attempts have been made to develop kappa-selective ligands from these structures and they are summarized here. 

Zhang A, NeumeyerJL, Baldessarini RJ. Recent progress in development of dopamine receptor subtype-selective agents Potential therapeutics for neurological and psychiatric disorders. Chem Rev 2007 107 274. 

The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

Innovative uses for novel, receptor subtype-selective vanilloids (see below), e.g. weight control. 

Wolohan, P., Reichert, D.E. CoMFAand Docking Study of Novel Estrogen Receptor Subtype Selective Ligands. J. Comput.-Aided Mol Des. 2003, 27, 313-328. 

Pharmacologically induced epileptiform activity in hippocampus slices can be used to assess the effect of 5-HT receptor-subtype-selective agonists and antagonist on network activity. To date, two studies have used this approach to understand how 5-HT4 and 5-HT7 could regulate hippocampal network activity (15,16). Activation of either 5-HT4 (15) or 5-HT7 (16) receptors increased coordinated epileptiform activity in this preparation, whereas activation of 5-HT1A receptors, which are also expressed in the hippocampus, suppressed it. The increases elicited by 5-HT4 and 5-HT7 receptors are consistent with those that could be predicted from the ability of these receptors to inhibit the sAHP in pyramidal cells (15,16). 

An example, where different receptor subtype selectivities have been observed for chemically related compounds, is presented in Fig. 3.7. The 5-HT3 receptor is a serotonin-controlled ion channel, whereas the 5-HT4 receptor is, like all other serotonin receptor subtypes, a GPCR. Despite a close chemical similarity, compound 31 is highly specific for the 5-HT3 receptor, having a more than 300-fold higher affinity to the 5-HT3 ion channel than to the 5-HT4 receptor (FQ 5-HT3 = 3.7 nM versus FQ 5-HT4 >1000 nM selectivity >250), while compound 32 binds almost exclusively to the 5-HT4 receptor (FQ 5-HT3 >10 000 nM versus FQ 5-HT4 = 13.7 nM selectivity >700) [30,31],... 

Mirza NR, Peters D, Sparks RG. 2003. Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Rev 9 159-186. 

Administration of drugs possessing receptor subtype selectivity. 

Table 2 Effectiveness of a selected experimental agent as an antagonist of [35S]GTP-y-S binding in guinea pig caudate stimulated by the opioid receptor subtype-selective agonists, DAMGO (p,), SNC80 (8), and U69,593 (k)...

Figure 2.15) show very different receptor subtype selectivities. Compound 53 has a more than 300-fold higher affinity for the 5-HT3 ion channel than for the G-protein-coupled 5-HT4 receptor (K 5-HT3 = 3.7 nM vs. Kt 5-HT4 > 1000 nM), whereas compound 54 binds almost exclusively to the 5-HT4 receptor (ff 5-HT3 >10 000 nM vs. K 5-HT4 =13.7 nM selectivity > 700) [28,29], The chemically related compound DF-1012, 55 (Figure 2.15), is an orally active antitussive drug [30],... 

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