Another source of variation is the oligomeric state of G protein-coupled receptors. In Figure 8.1, the receptor is depicted as a monomeric molecule, and indeed this was the prevailing model until fairly recently. However, it is now clear that very many GPCR are indeed oligomeric. This has several consequences:
• Efficacy and potency of a ligand may be different for monomeric and oligomeric receptors.
• Dose-effect curves may take different shapes, due to cooperative ligand binding4.
• Oligomers may be `homomers' but also `heteromers', which means that they may form from like or from dif ferent subunits. The existence of heteromers adds an-other dimension to the variability of receptor types, sim-ilar as with the voltage-gated potassium channels cov-ered earlier.
• It is possible to develop multivalent drugs that bind to several binding sites simultaneously. This may result in very high affinity for the receptor, and it might allow the targeting of certain heteromeric subtypes, increasing the selectivity of drug action.
An example of a bivalent drug that binds to the M1 mus-carinergic receptor is shown in Figure 8.4. The affinity of this molecule for the receptor is about 100 times higher than that of the conventional, monomeric agonist carba-chol. Note that there is a spacer between the two `pharma-cophores', which will allow the latter to bind to two sepa-rate subunits of the receptor oligomer. The length of this spacer was systematically varied, and it was found that a number of three repeating subunits gave both the highest affinity and the strongest receptor activation. Molecules with shorter spacers still bound with considerable affinity but failed to stimulate the receptor, possibly because the sterical constraint imposed by the shorter spacer prevented the receptor from assuming its active conformation. Since GPCR are all structurally related, this finding suggests a surprisingly straightforward approach to the development of agonistic and antagonistic drugs from a single `lead compound'.
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