Dcgiv

Antagonists LY 341495 ADBD (LY 307452) ADED (LY 310225)

Group III Agonists L-AP4 L-SOP

S-Homo-AMPA

Antagonist CPPG

abused substances (cf. ref. 160). Detailed reviews of the biochemistry, physiology, and pharmacology of the burgeoning field of mGluRs are available (160-166).

Although rapid progress has been made in the discovery of selective ligands for the eight mGluRs, the pharmacology of mGluRs is not fully developed (see Table 6). Although there are some compounds that have varying degrees of selectivity for each of the three groups of mGluRs, selectivity for any one of the eight members of the mGluR family has not yet been achieved. For example, the potent and selective group II agonist LY 354740 has micromolar affinity for two of the group III receptor subtypes. An additional complication arises from differences in efficacy. For example, benzyl-APDC is a selective agonist at mGlu6 receptors but demonstrates antagonist actions at mGlu2, mGlu3, and mGlu5 receptors. Furthermore, although new compounds with putative high selectivities have been reported, such as the stereoselective activation of mGluR4a and mGluR7b by (+)-4-phosphonophenyl-glycine, the overall selectivity profile and functional activities of these compounds remains to be characterized (167).

A variety of recent studies have examined the potential therapeutic efficacy of group I and group II mGluR ligands in the treatment of drug abuse. In contrast, the availability of selective compounds for the investigation of group III mGluRs is more limited, so less is known about the potential utilities of ligands for these receptors. For example, the group II agonist LY 354740 blocks PCP-induced stereo-typy, hyperlocomotion, and disruptions in memory without effects on spontaneous locomotion when given alone (168). Indeed, it appears that group II agonists may preferentially attenuate the motoric effects of PCP in comparison with the locomotor stimulation induced by d-amphetamine (cf. ref. 169). LY 35470 also attenuated the signs of nicotine and morphine withdrawal in dependent animals (cf. refs. 170 and 171) and can interfere with the development of tolerance to the analgesic effects of morphine (172). The group I antagonists MPEP and SIB 1893, which display selectivity for mGluR5, are effective anticonvulsants with favorable therapeutic indices (173); the role of these compounds in drug abuse has yet to be examined. In addition to a role for mGluR ligands in drug-abuse treatment, there is some evidence for alterations in the sensitivity of groups II and III mGluRs following chronic exposure to drugs of abuse like cocaine that have suggested their involvement in cocaine addiction and withdrawal (174).

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