Molecular determinants for ligand binding at serotonin 5‐HT_2A and 5‐HT_2C GPCRs: Experimental affinity results analyzed by molecular modeling and ligand docking studies

Abstract

Ligands that activate the serotonin 5-HT2C G protein-coupled receptor (GPCR) may be therapeutic for psychoses, addiction, and other neuropsychiatric disorders. Ligands that are antagonists at the closely related 5-HT2A GPCR also may treat neuropsychiatric disorders; in contrast, 5-HT2A activation may cause hallucinations. 5-HT2C-specific agonist drug design is challenging because 5-HT2 GPCRs share 80% transmembrane (TM) homology, same second messenger signaling, and no crystal structures are reported. To help delineate molecular determinants underlying differential binding and activation of 5-HT2 GPCRs, 5-HT2A, and 5-HT2C homology models were built from the β2-adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5-HT2 receptor models were conducted with the (2R, 4S)- and (2S, 4R)-enantiomers of the novel 5-HT2C agonist/5-HT2A/2B antagonist trans-4-phenyl-N,N-dimethyl-2-aminotetralin (PAT) and its 4′-chlorophenyl congners. Results indicate PAT–5-HT2 molecular interactions especially in TM domain V are important for the (2R, 4S) enantiomer, whereas, TM domain VI and VII interactions are more important for the (2S, 4R) enantiomer.

Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors

“…15 We determined previously that (−)- trans -PAT also is a functionally-selective histamine H 1 ligand that activates H 1 receptor-mediated adenylyl cyclase signaling but is an antagonist at H 1 -linked PLC signaling. 11 It is not clear what role histamine H 1 GPCRs may play in the psychotherapeutic effects of (−)- trans -PAT, however, H 1 and 5-HT 2 molecular modeling studies 16–20 suggest it is possible to reduce or eliminate H 1 affinity in PAT-type molecules, without compromising 5-HT 2 activity. For example, it was observed that especially the PAT C(4)-phenyl moiety docked differently at 5-HT 2A , 5-HT 2B , 5-HT 2C , and H 1 GPCRs 16–20 .…”

“…11 It is not clear what role histamine H 1 GPCRs may play in the psychotherapeutic effects of (−)- trans -PAT, however, H 1 and 5-HT 2 molecular modeling studies 16–20 suggest it is possible to reduce or eliminate H 1 affinity in PAT-type molecules, without compromising 5-HT 2 activity. For example, it was observed that especially the PAT C(4)-phenyl moiety docked differently at 5-HT 2A , 5-HT 2B , 5-HT 2C , and H 1 GPCRs 16–20 . Accordingly, here we report the synthesis of a series of novel PAT-type analogs with molecular changes at the C(4)-position, while preserving the N, N -dimethyl substitution at the 2-position, as well as, trans -stereochemistry, structural features previously shown to be optimal for binding to 5-HT 2 as well as H 1 GPCRs.…”

“…Accordingly, here we report the synthesis of a series of novel PAT-type analogs with molecular changes at the C(4)-position, while preserving the N, N -dimethyl substitution at the 2-position, as well as, trans -stereochemistry, structural features previously shown to be optimal for binding to 5-HT 2 as well as H 1 GPCRs. 16,18,20,21 Pharmacological affinity of the analogs at human recombinant 5-HT 2 receptor subtypes and H 1 receptors also are reported, as well as, molecular docking studies of selected analogs at a homology model of the 5-HT 2C receptor to help explain structure–affinity results. These studies were undertaken to facilitate design and development of drugs to treat the cognitive dysfunction common to a variety of neuropsychiatric disorders, including, psychoses, depression, dementia, as well as, substance abuse, attention-deficit hyperactivity, and other compulsive behavioral disorders.…”

Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

“…Position 1.42 is far from the orthosteric ligand binding pocket (Córdova-Sintjago et al, 2012a), and the functional and/or structural role of amino acids at position 1.42 is unknown. Amino acid residues in TMD5, however, have received attention due to their importance in ligand binding and function of GPCRs (Almaula et al, 1996a;van Rhee and Jacobson, 1996;Wang et al, 2013).…”

“…Nevertheless, the (2)-enantiomer showed significantly greater potency and efficacy for attenuating the 5-HT2A-dependent DOI-elicited HTR in mice. Docking studies of the 6-OH-7-Cl-PAT enantiomers at molecular models of 5-HT2A receptors (Córdova-Sintjago et al, 2012a) led to an examination of the putative role of 5-HT2A residue 5.46 in mediating (1)-6-OH-7-Cl-PAT ligand affinity and function. The results pinpoint a single amino acid difference at position 5.46 in the m5-HT2A and h5-HT2A receptor that impacts translation of novel PAT drug candidates for neuropsychiatric disorders.…”