Structural basis of the selectivity of the β2-adrenergic receptor for fluorinated catecholamines

Abstract

The important and diverse biological functions of adrenergic receptors, a subclass of G-protein coupled receptors (GPCRs), have made the search for compounds that selectively stimulate or inhibit the activity of different adrenergic receptor subtypes an important area of medicinal chemistry. We previously synthesized 2-, 5-, and 6-fluoronorepinehprine (FNE) and 2-, 5-, and 6-fluoroepinephrine (FEPI) and found that 2FNE and 2FEPI were selective β-adrenergic agonists and that 6FNE and 6FEPI were selective α-adrenergic agonists, while 5FNE and 5FEPI were unselective. Agonist potencies correlated well with receptor binding affinities. Here, through a combination of molecular modeling and site-directed mutagenesis, we have identified N293 in the β 2 -adrenergic receptor as a crucial residue for the selectivity of the receptor for catecholamines fluorinated at different positions.

Progress in Structure Based Drug Design for G Protein-Coupled Receptors

“…62,63 The binding pockets for cyanopindolol and carazolol are very similar in the two receptors, which have a high level of sequence conservation in the transmembrane domain regions (Table 3, entries 2 and 3). In fact, in the binding site there are 15 amino acid residues that in β 1 AR are in contact with cyanopindolol and that are conserved in β 2 AR.…”

GPCR agonist binding revealed by modeling and crystallography

“…Conversely, other docking and modeling studies supported much smaller changes in the inactive crystal structure of the β 2 AR upon agonist binding [45]. Thus, the initial agonist-induced fit can be modeled by changing only rotameric states of serine side chains in TM5 [16, 17, 28], though these changes were thought to represent low-affinity binding mode of agonists.…”

Effects of Aromatic Fluorine Substitution on Protonated Neurotransmitters: The Case of 2‐Phenylethylamine

“…For example, ring fluorination of noradrenaline modifies the α‐ and β‐adrenergic agonist properties of this neurotransmitter . Furthermore, the substitution site strongly controls the (re)activity of these compounds …”

“…[19,20] Furthermore, the substitutions ite strongly controls the (re)activity of these compounds. [20,21] 2-Phenylethylamine (PEA) is the parentmolecule of the large class (> 200) of aromatic ethylamino neurotransmitters, including dopamine, serotonin, adrenaline, and other psycho-active drugs such as amphetamines.N eurotransmitters are chemical messenger compounds responsible for signal transmission, enhancement, and modulation in living organismse ndowed with ac entral nervouss ystem.I np articular,P EA acts as an eurotransmitter in the central nervous system of mammalians. [22][23][24] For example, it increases the synaptic levels of dopamine and directly interacts between dopaminergic neurons.…”