The Sreceptor

Opioid peptides for the S-receptor include the endogenous peptides described previously, Met and Leu enkephalin, as well as some synthetic peptides such as DADLE, DSLET, and DPDPE (see Fig. 24.2 for amino acid sequences). These pep-tides have high affinity for the receptor but low bioavailability and thus limited clinical usefulness. They are used in animal in vitro studies as probes for S-receptor location and function.

In an attempt to distinguish the amino acids responsible for S-receptor ligand specificity, point mutations of the S-receptor, and //S-receptor chimeras were constructed.38 The altered receptors had a decreased ability to bind to S-receptor selective peptide and nonpeptide ligands, when amino acids in the extracellular top of TM6 and TM7 and the extracellular loop (EC loop 3) that connected them were mutated.

Specifically, amino acids Try284, Val296, and Val297 were crucial to selective S-ligand binding. These amino acids may provide recognition sites on the receptor that the ligand would have to pass through to reach the putative binding site deeper in the TM cavity. Befort et al.39 also used site-directed point mutant receptors along with molecular modeling to identify Tyr129 in tM3 as the most crucial amino acid for ligand binding. In addition, they found a role for amino acid Tyr308 (TM7) in ligand binding.

Nonpeptide agonists and antagonists have been designed to further study the function of the S-receptor. The first non-peptide lead compound selective for the S-receptor came from screening. Modifications to the lead compound led to the identification of SNC-80 as a potent agonist specific for the S-receptor (Fig. 24.4). This compound has weak antinoci-ceptive effects in monkeys, an effect that can be reversed with the S-antagonist naltrindole (NTI) (Fig. 24.4).40 A series of SNC-80 analog, prepared by multiple groups, found that the amide nitrogen appears to be the most sensitive to modifications and may play an important role in S-receptor selectiv-ity.41 Portoghese designed 7-spiroindanyloxymorphone (SIOM) (Fig. 24.4) based on the idea that the indole of NTI is acting as an "address" mimic of the Phe4 phenyl group of enkephalin. The "address-message" concept proposes that one part of the molecule may act as an "address," essentially directing the chemical to the correct receptor by binding specifically to that receptor, and another part of the molecule acts as the "message," which gives the compound the biological action. The indole of NTI was replaced with a spiroindane functional group equivalent address in SIOM. The N-methyl group of SIOM confers an agonist message as opposed to the antagonist message of the NTI cyclopropyl methyl.42 Additional agonists for the S-receptor have been

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