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Medicinal ChemistryThis page describes the current research in our lab to better understand the molecular mechanisms involved in receptor-ligand interactions. For this purpose we use This particular page contains data from the following paper:
in which the concept of "privileged structures" is used to convert a highly potent, and moderately A3 selective (vs either A1 or A2A receptors, but not calcium channels), calcium channel blocker into a potent and very selective A3 antagonist (vs any other binding site tested).
IntroductionThe 1,4-dihydropyridines (DHPs) have been developed extensively as potent blockers and activators of L-type calcium channels. A number of these channel blockers, such as nifedipine (Figure 1, 7) and nicardipine (Figure 1, 10), are used therapeutically in the treatment of cardiovascular disorders, especially hypertension and coronary heart disease.
DHPs appear to be "privileged structures" in medicinal
chemistry and pharmacology, i.e. they display affinity for many diverse
binding sites. This adaptability of DHPs has been utilized to optimize
affinity in binding to
Studies of the structure-activity relationship of xanthines at A3 adenosine receptors have thus far failed to identify principles of achieving receptor subtype selectivity. In the current study, we aim to show that the affinity of DHPs can be optimized selectively for adenosine receptors versus L-type calcium channels and for A3 versus A1 and A2A adenosine receptors.
Results & DiscussionStructure-activity relationship (SAR; Table 1) analysis at adenosine receptors indicated that sterically bulky groups are tolerated at the 4-, 5-, and 6-positions. Compound 3 is a potent PAF-acether antagonist and not a calcium channel ligand, thus there is an uncoupling of the SAR in this series for interaction with both PAF and adenosine receptors on the one hand and L-type calcium channels on the other hand.In a series of methyl (1), n-propyl (4), and even larger alkyl substituents (5) at the 4-position it was demonstrated that steric bulk at this position is tolerated in adenosine receptor binding, favored at the A3 subtype, and not detrimental at the A1 subtype. In general, the affinity and receptor subtype selectivity of 4-aryl analogues was highly dependent on the substituents of the phenyl ring. Compound 14, bearing an ortho-trifluoromethyl group behaved similarly to the ortho-nitro substituted compound 8, and was 2-fold selective for A1 vs A3 receptors. The piperonal derivative 17 had a generally increased affinity at A1 and A3 adenosine receptor subtypes, but did not display subtype selectivity. The relatively high affinity of a 4-aryl group larger than phenyl (17), an arylalkyl group (18), and dehydro analogues thereof (19, 22) further indicated a bulk tolerance at this position.
The 4-trans-
Table 1: Affinities of dihydropyridines at A1, A2A, and A3 receptors in Ki (µM) ± sem.a-e
a) Displacement of specific [3H]PIA binding in rat brain
membranes.
Affinities of enantiomeric pairs (12,13 & 15,16)
indicated a general preference for the R- over the S- enantiomer
at all of the receptor subtypes. This is in contrast to the affinity at L-type
calcium channels and at At the 6-position, n-butyl substitution (20) was tolerated, and phenyl substitution (21) enhanced A3 adenosine receptor binding (4.5-fold vs 1), and lead to slight subtype selectivity.
Combination of 6-phenyl and
4-trans-
Table 2: Specifity for L-type Calcium Channels.a
a) Inhibition of specific [3H]isradipine binding at L-type calcium channels in rat brain membranes expressed in µM as Ki ± sem or percent displacement of specific binding at the indicated concentration (M), and the selectivity ratio versus affinity at cloned human A3 receptors. Moreover , MRS1097 (22) was 1000-fold selective for A3 adenosine receptors vs L-type Ca2+-channels (Table 2), displaced less than 10 % of total [3H]NBI binding from the Na+- independent adenosine transporter in rat forebrain at a concentration of 10-4 M (data not shown), and was able to reverse N6-(3- iodobenzyl)adenosine-5'-N-methyluronamide induced inhibition of forskolin- stimulated adenylyl cyclase in CHO cells transfected with rat A3 adenosine receptors (Figure 2).
In addition to the aforementioned assays, the affinity of MRS1097 (22) was evaluated in a battery of radioligand binding assays (NovaScreen®, Div. of Oceanix Biosciences, Hanover, MD) at a concentration of 10-5 M (Table 3).
Table 3: Binding Sites with Negligible Affinity for MRS1097 (22)a
a) Displacement of < 25 % of the specific ligand from the relevant binding site.
Conclusions
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1a-adrenergic receptors
(e.g., the antagonist SNAP 5089, Figure 1), and to platelet activating factor
(PAF) receptors (Figure 1, 3). Thus, by careful structural modification,
it has been possible to select for affinity at sites other than
Ca2+-channels.
-styryl
derivative, 19, was particularly potent and selective at human
A3 receptors. Nicardipine, 10, differing from nitrendipine,
8, in the presence of a sterically bulky ester group at the 5-position,
displayed a moderate enhancement of affinity at human A3 receptors
of 2.6-fold, while at rat A1 and A2A receptors affinity
was diminished 2-3 fold.
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