Selectivity of 5HT2C Antagonist and Agonist Ligands over the Monoamine Receptor Family and the 5HT Receptor Subfamily

In regards with a multiple sequence alignment (Fig. 6.5) of the human 5-HT receptor subtypes with several members of human GPCR-type monoamine receptors -►

Fig. 6.5 (continued) DRD1-5 (dopamine receptor ranging from type D1 to D5) and HRH1 (Hl-histamine receptor). The critical amino acid residues for ligand binding are overlined and annotated as the Ballesteros and Weinstein numbering system, whereas the consensus sequence is shown at the bottom of each segment, along with a plot showing the degree of similarity at each residue position

Fig. 6.5 Critical amino acids for monoamine receptors and the 5-HT2C selectivity. Three relevant regions of human 5-HT2C sequence (surrounded in a dashed frame) are aligned with human GPCR-type serotonin receptors and several members of human GPCR-type monoamine receptors, ADA1A (a1-adrenoceptor), ADA2A (a2-adrenoceptor), ADRB1 (b1-adrenoceptor), ADRB2 (^-adrenoceptor),

Fig. 6.5 Critical amino acids for monoamine receptors and the 5-HT2C selectivity. Three relevant regions of human 5-HT2C sequence (surrounded in a dashed frame) are aligned with human GPCR-type serotonin receptors and several members of human GPCR-type monoamine receptors, ADA1A (a1-adrenoceptor), ADA2A (a2-adrenoceptor), ADRB1 (b1-adrenoceptor), ADRB2 (^-adrenoceptor),

(dopamine, histamine, or adrenalin receptors), we expect to provide some insights on single or groups of amino acid residues conferring a ligand selectivity for the human 5-HT2C receptor relatively to closest other subtypes. Focusing on the interactions previously picked in at least two models from TM2 to TM7, Trp3.28, Leu3.31, Val3.33, Phe5.38, Val5.39, Ser5.43, Ile5.49, Asn6.55, Asn7.36, and Tyr7.43 are not strictly conserved, but all variants are homologous according to their intrinsic properties of interaction, either aromatic (electronic p-p stacking contact), VdW (atomic contact) hydrophobic interactions, or ionic and hydrogen-bonding polar interactions. Phe3.35 and Ser3.36 appeal to us because they are homologous only among the 5-HT2 subtypes and shift from aromatic and polar, respectively, toward VdW intrinsic properties. Other lonely interactions in different models like Ile4.60, Pro4.61, and Val7.39 are also homologous, whereas Ala2.64 is the only TM residue to divert from the polar amino acids of all the other receptors at this position.

Looking for all amino acids previously mentioned to bond either antagonist or agonist ligands shows that very few of these aligned residues are found solely in the human 5-HT2C receptor. Even Trp120 of extracellular loop EL1, which specifically hydrogen bonds with the more selective antagonists in our ADRB-based model, is strictly conserved among all the studied sequences. The only cluster to be clearly involved in selective interactions of 5-HT2C with ligands is the EL2 loop. Indeed, even though Asn204 and Thr205 are also found in EL2 of 5-HT2B, the alignment match with ADRB2 and D5 can not be considered because of the consequent variation of the loop length that may render their 3D folding very different in this central region of the loop. On the contrary, the N-terminal or C-terminal residues of the loops get reliably less freedom of 3D folding due to their closeness to the spatially constrained a-helices. Thus, Asn210, the last C-terminal residue of EL2, is conserved in 5-HT1B, 5-HT1D and a-adrenoceptors and should be thus considered as a common structural feature, whereas Arg195, the fourth N-terminal residue of EL2, is not conserved and could therefore be labeled as a selective structural feature for the 5-HT2C subtype, enabling it to be targeted by selective ligands.

Consequently, drug design of 5-HT2C selective ligands should first respect the essential 3D pharmacophore common to GPCR-type monoamine receptors and integrate the discussed structural features to selectively target 5-HT2C. As in most type-A GPCR receptors, antagonists are more voluminous than agonists are in that they should neutralize all interaction spots in a ligand binding cavity in order to prevent the unlocking and activation of the receptor. Thus, the design of 5-HT2C antagonists should integrate a central dipolar chemical group to consolidate specific interactions downward with D3.32, S3.36, and Y7.43 and especially earning hydrogen bonds upward with E2 loop (Arg195, Asn204, Thr205) and then two terminal aromatic ring assemblies targeted by aliphatic groups to earn specific VdW interactions in the hydrophobic cluster (Ala2.64, Trp120, Trp3.28). Agonists should be truncated from this aromatic pharmacophoric element to focus only on the dipolar group and one aromatic ring assembly near the TM5-TM6 aromatic cluster.

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