The A 3 Adenosine Receptor: History and Perspectives

Journal of Pharmacology and Experimental Therapeutics

Eshleman

2016

Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [ potent DA uptake inhibitor (compound 6) with an IC 50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 49-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake.

Section: Introductionmentioning

confidence: 99%

Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

Janowsky

Journal of Pharmacology and Experimental Therapeutics

Eshleman

2016

“…Most informative is the observation that N 6 -Rphenylisopropyladenosine-induced hypothermia was attenuated in adenosine A 3 receptor (A 3 AR) null (Adora3 2/2 ) mice, directly implicating the A 3 AR's involvement in hypothermia (Yang et al, 2010). In rodents, the A 3 AR is expressed in neutrophils, basophils, mast cells, and other cells mediating inflammatory responses (Borea et al, 2015). Use of Adora3 2/2 mice conclusively demonstrated a role for A 3 AR in triggering mouse mast cell degranulation , whereas the A 3 AR may not be important in human mast cell degranulation (Auchampach et al, 1997;Gomez et al, 2011;Rudich et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

Carlin

Journal of Pharmacology and Experimental Therapeutics

Xiao

et al. 2015

Adenosine can induce hypothermia, as previously demonstrated for adenosine A 1 receptor (A 1 AR) agonists. Here we use the potent, specific A 3 AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A 3 AR. The hypothermic effect of A 3 AR agonists is independent of A 1 AR activation, as the effect was fully intact in mice lacking A 1 AR but abolished in mice lacking A 3 AR. A 3 AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A 3 AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brainpenetrant agonist caused hypothermia, suggesting that peripheral A 3 AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H 1 (but not H 2 or H 4 ) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A 3 AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A 3 AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H 1 receptors to induce hypothermia. This mechanism suggests that A 3 AR agonists will probably not be useful for clinical induction of hypothermia.

“…5 The affinities (nM; m, c; mean ± SEM, n = 3) were: 10, (36 ± 5, 5 8.5 ± 0.7); 11, (27 ± 2, 1.5 ± 0.2); 12, (6.8 ± 0.3, 5.8 ± 0.2); 19 (31 ± 2, 75 ± 7); 20 (16 ± 3, 49 ± 4). Thus, 12 was consistently potent in binding at h and mA 3 ARs. Off-target activity at various receptors (Psychoactive Drug Screening Program, 20 Supporting Information) indicated only an occasional interaction in the micromolar range.…”

mentioning

confidence: 83%

Rigidified A₃ Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy

Crane

Chen

et al. 2015

ACS Med. Chem. Lett.

Substitution of rigidified A 3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in place of ribose, which adopts a receptor-preferred conformation. N 6 -Small alkyl derivatives were newly optimized for A 3 AR affinity and the effects of a 1-deaza-adenine modification probed. 1-Deaza-N 6 -ethyl alkyne 20 (MRS7144, K i 1.7 nM) and 1-aza N 6 -propyl alkyne 12 (MRS7154, K i 1.1 nM) were highly efficacious in vivo. Thus, the presence of N1 is not required for nanomolar binding affinity or potent, long-lasting functional activity. Docking of 1-deaza compounds to a receptor homology model confirmed a similar binding mode as previously reported 1-aza derivatives. This is the first demonstration in nonribose adenosine analogues that the 1-deaza modification can maintain high A 3 AR affinity, selectivity, and efficacy.