TABLE 4

Comparison of ligand-binding pocket of mGlu5 allosteric antagonist with those of cis-retinal-binding pocket of rhodopsin or in other previously reported modulators of group I mGlu receptors or in inverse agonist of h5HT4 receptor

The 18 residues located at a distance of 4.5 Å from cis-retinal in the 3D structure of rhodopsin are shown (Palczewski et al., 2000; Teller et al., 2001; Sakmar et al., 2002). The generic numbering system proposed by Ballesteros and Weinstein (1995) was used to compare residues in the 7TMD of the different GPCRs. The residues that have been reported to be located in the binding-sites are [3H]M-MPEP. of hmGlu5a (Pagano et al., 2000); [3H]EM-TBPC of rmGlu1 α (Malherbe et al., 2003); (−)-CPCCOEt of hmGlu1b (Litschig et al., 1999); RO 67-7476 of rmGlu1α (Knoflach et al., 2001); and inverse agonist of h5HT4 receptor (Joubert et al., 2002).

7TMD Position Rhodopsin cis-Retinal Rat mGlu5a [3H]MPEP Human mGlu5a [3H]M-MPEP Rat mGlu1α [3H]EM-TBPC Human mGlu1b (−)-CPCCOEt Rat mGlu1α RO 67-7476 Human 5HT4R Inverse Agonist
TM3
3.28 Glu-113
3.32 Ala-117 Asp-100
3.33 Thr-118
3.36 Gly-121 Pro-654 Pro-655 Ser-668
3.37 Glu-122
3.39 Ser-658
3.4 Tyr-658
EC2
45.44 Glu-181
45.49 Ser-186
45.54 Tyr-191
TM5
5.42 Met-207
5.46 His-211
5.47 Phe-212 Leu-743 Val-757 Val-757
TM6
6.44 Phe-261 Thr-780
6.48 Trp-265 Trp-784 Trp-798 Trp-272
6.51 Tyr-268 Phe-787 Phe-801 Phe-275
6.52 Ala-269
6.55 Ala-272 Tyr-791 Tyr-805
TM7
7.39 Ala-292 Thr-815 Thr-815
7.42 Ala-818
7.43 Lys-296
7.47 Ala-809 Ala-810