Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.

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Administration of meprobamate to suitable patients produces both tranquilization and muscular relaxation (Berger, 1956). Since elimination of one of these two actions not only could yield new and useful drugs, but might also shed some light on the interrelation between psychic and somatic tension, numerous compounds chemically related to meprobamate (Berger, 1954) were synthesized and subjected to pharmacological evaluation. Of these, N-isopropyl-2-methyl-Zpropyl-l , 3-propanediol dicarbamate (FIGURE l), called carisoprodol (Soma, Rela), which differs from meprobamate in having an isopropyl group in place of a hydrogen atom on one of the carbamyl nitrogens, appeared of unusual interest (Berger, 1959). This relatively simple substitution yielded a compound that was surprisingly unlike meprobamate in pharmacological properties (Berger el al., 1959). Carisoprodol not only had an entirely different profile of effects on the central nervous system but, in addition, unexpectedly exhibited analgesic properties of an unusual kind.I t melts without decomposition at 92O to 94" C. and dissolves in water to the extent of 0.3 mg./ml. at 25" C. and 1.4 mg./ml. at 50" C. It is readily soluble in common organic solvents, but almost insoluble in liquid fats. On boiling with strong acid or alkali, carisoprodol is hydrolyzed to ammonia, isopropylamine, carbon dioxide, and 2-methyl-2-propyl-l , 3-propanediol. I t is stable in dilute acid and alkali, and is not altered by gastric or intestinal juices at 37" C. Eject oj Carisoprodol on the Central Nervous SystemThe effect of carisoprodol on the electroencephalogram was investigated in unanesthetized cats and rabbits. Cats were anesthetized with ether and bipolar electrodes were placed stereotaxically into various subcortical structures. Needle electrodes were used for cortical recordings. All wound margins were infiltrated with lidocaine, and recordings were begun only after at least one hour had elapsed to allow for elimination of ether. The animals were immobilized with succinylcholine given continuously by intravenous infusion. The drugs, dissolved in 50 per cent propylene glycol, were injected intravenously. In rabbits all surgical procedures were carried out under local anesthesia and the animals were not curarized.Administration of carisoprodol in doses of 5 to 10 mg./kg. produced a marked decrease in frequency and an increase of amplitude in cortical and subcortical recordings (FIGURE 2). Spindling was seldom seen. Meprobamate in similar doses, in agreement with previously published work, had no effect on the brainwave patterns (Hendley el al., 1954, 1957; Gangloff, 1958, 1959).Larger doses of carisoprodol caused progressive slowing of frequency and an increase of amplitude until, after a dose of approximately 40 to 60 mg./kg., there 90 Carisoprodol is a bitter, essentially odorless, white crystalline powder. Effect on the electroencephalogram and behavior.

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