ChemInform Abstract: Ribose‐Modified Adenosine Analogues as Adenosine Receptor Agonists.

Taylor, Michael D.; Moos, Walter H.; Hamilton, Harriet W.; Szotek, Deedee S.; Patt, William C.; Badger, Edward W.; Bristol, James A.; Bruns, Robert F.; Heffner, Thomas G.; Mertz, Thomas

doi:10.1002/chin.198649330

Cited by 16 publications

(32 citation statements)

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“…In particular, N 6 -(3-iodobenzyl)adenosine derivatives are highly potent and selective ligands for this receptor. Modification of the ribose moiety affects the intrinsic activity of compounds [Taylor et al, 1986;Daly and Padgett, 1992]. In a recent study from our laboratories on the adenosine A 1 receptor [Van der Wenden et al, 1998], substitution of the A 1 selective ligand N 6 -cyclopentyladenosine (CPA) with alkylthio-and alkylseleno groups at the ribose 5′position led to compounds which behaved as partial ago-nists for the A 1 receptor.…”

Section: Introductionmentioning

confidence: 99%

Medicinal chemistry of the human adenosine A3 receptor

1998

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Partial agonists and antagonists were synthesized and evaluated biologically for extended pharmacologic characterization of the human adenosine A3 receptor. The affinities of all compounds were determined at the human adenosine A3 receptor stably transfected in HEK 293 cells and in rat brain membranes for the adenosine A1 and A2A receptors. The partial agonists were also evaluated for their ability to stimulate [35S]GTPγ[S] binding in Chinese hamster ovary cells expressing the human adenosine A3 receptor to determine their intrinsic activities. 5′‐(Alkylthio)‐substituted analogs of N6‐(3‐iodobenzyl)adenosine were synthesized in 47–60% overall yields. The compounds proved to be potent and selective partial agonists for the A3 receptor, displaying affinities in the nanomolar range. N6‐(3‐iodobenzyl)adenosine (2), 5′‐deoxy‐N6‐(3‐iodobenzyl)‐5′‐methyl‐thioadenosine (4), and 5′‐deoxy‐N6‐(3‐iodobenzyl)‐5′‐ethylthioadenosine (5) had highest affinities for the A3 receptor with Ki values ranging from 9–28 nM. Compound 6 (5′‐deoxy‐N6‐(3‐iodobenzyl)‐5′‐n‐propyl‐thioadenosine) had the highest (over 200‐fold) A3 receptor selectivity. Of all partial agonists, 2 and 4 had the highest intrinsic activities. Subsequently, a series of 3‐(2‐pyridinyl)isoquinoline derivatives was synthesized as potential antagonists for the human adenosine A3 receptor. A structure‐activity relationship was performed at the 1‐position of this series. This analysis indicated that a phenyl group, when coupled by a spacer allowing conjugation on position 1 of the isoquinoline ring, increased the adenosine A3 receptor affinity. Of all spacers tested, a carboxamide proved to be optimal. N‐[2‐(2‐pyridinyl)isoquinolin‐4‐yl]‐benzamide (9) had an affinity of 200 nM at the adenosine A3 receptor. Furthermore, the effects of mono‐ and disubstitution of the benzamide ring of 9 were investigated. This led to the A3‐selective compound 4‐methoxy‐N‐[2‐(2‐pyridinyl)quinazolin‐4‐yl]‐benzamide (18) with an affinity of 17 nM at the human adenosine A3 receptor. These partial agonists and antagonists may be useful tools in the pharmacologic characterization and the investigation of the physiologic function of this receptor. Drug Dev. Res. 45:182–189, 1998. © 1998 Wiley‐Liss, Inc.

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Section: Introductionmentioning

confidence: 99%

Medicinal chemistry of the human adenosine A3 receptor

1998

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“…Adenosine agonists inhibit spontaneous locomotion (Vapaatalo et al 1975;Snyder et al 1981 ;Barraco et al 1983), food intake (Levine and Morley 1982), and conditioned behaviors (Coffin et al 1984;Coffin and Spealman 1985;Glowa et al 1985;Coffin and Carney 1986). Involvement of adenosine receptors is suggested by the high affinity for these receptors displayed by behaviorally active adenosine analogs (e.g., Bruns et al 1986), the lack of behavioral activity seen with analogs that lack adenosine receptor affinity (Taylor et al 1986), and the reversal of these effects by adenosine antagonists (Coffin etal. 1984;Glowa etal.…”

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confidence: 96%

Comparison of the behavioral effects of adenosine agonists and dopamine antagonists in mice

Heffner¹,

Wiley²,

Williams³

et al. 1989

Psychopharmacology

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The adenosine agonists 5'-N-ethylcarboxamideadenosine (NECA), 2-chloroadenosine (2-CLA), N6-cyclohexyladenosine (CHA), N6-cyclopentyladenosine (CPA), 2-(phenylamino)adenosine (CV-1808) and R and S isomers of N6-phenylisopropyladenosine (R-PIA and S-PIA) decreased spontaneous locomotor activity in mice and, except for CPA, did so at doses that did not impair motor coordination, a profile shared by dopamine antagonists. CV-1808, the only agent with higher affinity for A2 as compared with A1 adenosine receptors, displayed the largest separation between locomotor inhibitory and ataxic potency. Like dopamine antagonists, NECA and CV-1808 also decreased hyperactivity caused by d--amphetamine at doses that did not cause ataxia whereas A1-selective adenosine agonists reduced amphetamine's effects only at ataxic doses. Unlike dopamine antagonists, adenosine agonists inhibited apomorphine-induced cage climbing only at doses that caused ataxia. Involvement of central adenosine receptors in these effects was suggested by the significant correlation obtained between potency for locomotor inhibition after IP and ICV administration. Affinity for A1 but not A2 adenosine receptors was significantly correlated with potency for inducing ataxia. These results suggest that the behavioral profile of adenosine agonists in mice is related to their affinity for A1 and A2 adenosine receptors and indicate that adenosine agonists produce certain behavioral effects that are similar to those seen with dopamine antagonists.

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“…However, much less is known about the requirements foragonist activity at the A 1 receptor. Sturlies with adenine (Ebert and Schwabe, 1973), 9-substituted adenine derivatives (Ukena et al, 1987) and ribose-modified adenosine analogues (Trost and Stock, 1977;Taylor et al, 1986) have pointed to the importance of the ribose moiety both for binding affinity and agonist effects .. In the present study we report that removal of the 2'-and 3' -hydroxy groups of the potent full A 1 receptor agonist, N 6 -cyclohexyladenosine (CHA), is sufficient to completely abolish its agonist activity.…”

Section: Introductionmentioning

confidence: 66%

“…Thus, ddCHA isapure antagonist at both adenosine receptor subtypes, with a 20-to 30-fold selectivity for the A 1 receptor. Removal of the 3'-hydroxy group from R-PIA has been shown to result only in a moderate loss of affinity and the retention of at least partial agonist affinity (Taylor et al, 1986). Removal of the 2'-hydroxy group from adenosine (Trost and Stock, 1977) or R-PIA (Taylor et al, 1986) results in a marked loss of affinity, but some agonist affinity appears to remain (Trost and Stock, 1977).…”

Section: Discussionmentioning

confidence: 99%

“…Removal of the 3'-hydroxy group from R-PIA has been shown to result only in a moderate loss of affinity and the retention of at least partial agonist affinity (Taylor et al, 1986). Removal of the 2'-hydroxy group from adenosine (Trost and Stock, 1977) or R-PIA (Taylor et al, 1986) results in a marked loss of affinity, but some agonist affinity appears to remain (Trost and Stock, 1977). At the A 2 receptor of human fibroblasts, 3' -deoxyadenosine has been reported to act as a partial agonist and non-competitive inhibitor of the adenosine-induced increase of cAMP and 2' -deoxyadenosine has been reported to act as a non-competitive inhibitor (Bruns, 1980).…”

Section: Discussionmentioning

confidence: 99%

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2′,3′-Dideoxy-N6-cyclohexyladenosine: an adenosine derivative with antagonist properties at adenosine receptors

Klotz¹,

Diekmann

Friedrich

et al. 1988

European Journal of Pharmacology

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Tbe 2',3'-dideoxy analogue of the potent A 1 receptor agonist, N 6 -cyclohexyladenosine (CHA), was synthesized as a potential antagonist for the A 1 adenosine receptor. In sturlies on adenylate cyclase 2',3'-dideoxy-N 6 -cyclohexyladenosine (ddCHA) did not show agonist properties at A 1 or at A 2 receptors. However, it antagonized the inhibition by R-PIA of adenylate cyclase activity of fat cell membranes via A 1 receptors with a Ki value of 13 .uM. ddCHA competed for the binding of the selective A 1 receptor antagonist, [ 3 HJ8-cyclopentyl-1,3-dipropylxantbine, to rat brain membranes with a Ki value of 4.8 I'M; GTP did not affect the competition curve. In contrast to the marked stereoselectivity of the A 1 receptor for the cx-and the natural ß-anomer of adenosine, the cx-anomer of ddCHA showed a comparable affinity for the A 1 receptor (K 1 value 13.9 ILM). These data indicate that the 2'-and 3'-hydroxy groups of adenosine and its derivatives are required foragonist activity at and high affinity binding to A 1 adenosine receptors and for the distinction between the cx-and ß-forms.

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ChemInform Abstract: Ribose‐Modified Adenosine Analogues as Adenosine Receptor Agonists.

Cited by 16 publications

References 1 publication

Medicinal chemistry of the human adenosine A3 receptor

Medicinal chemistry of the human adenosine A3 receptor

Comparison of the behavioral effects of adenosine agonists and dopamine antagonists in mice

2′,3′-Dideoxy-N6-cyclohexyladenosine: an adenosine derivative with antagonist properties at adenosine receptors

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