N⁶-Cycloalkyl- and N⁶-Bicycloalkyl-C5′(C2′)-modified Adenosine Derivatives as High-Affinity and Selective Agonists at the Human A₁ Adenosine Receptor with Antinociceptive Effects in Mice

Abstract

To further investigate new potent and selective human A(1) adenosine receptor agonists, we have synthesized a series of 5'-chloro-5'-deoxy- and 5'-(2-fluorophenylthio)-5'-deoxy-N(6)-cycloalkyl(bicycloalkyl)-substituted adenosine and 2'-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A(1), A(2A), A(2B), and A(3) adenosine receptors. In the series of N(6)-cyclopentyl- and N(6)-(endo-norborn-2-yl)adenosine derivatives, 5'-chloro-5'-deoxy-CPA (1) and 5'-chloro-5'-deoxy-(+/-)-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA(1) vs the other human receptor subtypes. The higher affinity and selectivity of 5'-chloro-5'-deoxyribonucleoside derivatives 1 and 3 for hA(1) AR vs hA(3) AR compared to that of the parent 5'-hydroxy compounds CPA and (+/-)-ENBA was rationalized by a molecular modeling analysis. 5'-Chloro-5'-deoxy-(+/-)-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p.

Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms

“…Cl-ENBA is the most selective A 1 AR agonist described, with ~2600-fold selectivity for binding to human A 1 AR vs. A 3 AR (Franchetti et al , 2009; Trivedi et al , 1989) and ~10,000-fold selectivity for mouse A 1 AR over A 3 AR (Table 1). Cl-ENBA (0.3–10 mg/kg, i.p.)…”

“…Cl-ENBA is a more selective A 1 AR agonist than CPA, CHA, and MRS5474 in the mouse for binding (Franchetti et al , 2009; Trivedi et al , 1989) (Table 1) and in vivo hypothermia. At 1 mg/kg i.p., Cl-ENBA was largely selective for A 1 AR, although at 3 mg/kg some of the effect was contributed by A 3 AR.…”

“…The following compounds (vehicle) were purchased from Sigma (St. Louis, MO) or Tocris (Minneapolis, MN): Cl-ENBA, (±)-5'-chloro-5'-deoxy- N 6 - endo -norbornyladenosine (Franchetti et al , 2009; Trivedi et al , 1989) (10% DMSO in saline); CHA, N 6 -cyclohexyladenosine (dissolved in DMSO, then diluted to 10% DMSO with saline); CPA, N 6 -cyclopentyladenosine (saline); pyrilamine (saline); AMP, adenosine 5'-monophosphate (saline); CCPA, 2-chloro- N 6 -cyclopentyladenosine. MRS5474, (1R,2R,3S,5S)-4-(2-chloro-6-((dicyclopropylmethyl)amino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol, (dissolved in DMSO, then diluted with 9 volumes 30% PEG400) was synthesized as described (Tosh et al , 2012b).…”

Medicinal chemistry of adenosine, P2Y and P2X receptors

“…A 1 -selective nonnucleoside derivative capadenoson (BAY68-4986) 9 is in trials for treatment of persistent atrial fibrillation and is now available as a research tool (Tendera et al ., 2012). Compound 10 is highly selective for the A 1 AR and displayed analgesic activity in the formalin test in mice (Luongo et al , 2012, Franchetti et al , 2009). Compound 11 is a peripherally-selective agonist, due to its permanently charged sulfonate group, that is moderately A 1 AR selective (70-fold).…”

Synthesis of Triazole-Linked Analogues of c-di-GMP and Their Interactions with Diguanylate Cyclase

“…Similarly, the protected 5'-azido-5'-deoxy-guanosine 3 was reacted with N 6 -benzoyl-2',3'-O-isopropylidene-5'-O-propargyl-adenosine (9) 34 , to obtain the intermediate 11. The 5'-azido-5'-deoxy-2',3'-O-isopropylidene-adenosine (5) 35 , prepared starting from 2',3'-Oisopropylidene-adenosine (2) [36][37][38][39][40] was clicked with 8 and 9 to furnish the 1,2,3-triazole intermediates 12 and 13, respectively. Compound 10 was first deprotected in acidic conditions and then in saturated ammonium hydroxide solution at 50°C, to give, after purification, the triazolelinked dinucleoside DCI028.…”