Search

8-(Sulfostyryl)xanthine derivatives were synthesized as water-soluble A2A-selective adenosine receptor (AR) antagonists. meta- and para-sulfostyryl-DMPX (3,7-dimethyl-1-propargylxanthine) derivatives 11a and 11b exhibited high affinity to rat A2A-AR in submicromolar concentrations, and were 20- to 30-fold selective versus rat A1-AR. Styryl-DMPX derivatives were inactive at human A2B- and A3-AR. 1,3-Dipropyl-8-p-sulfostyrylxanthine (13) and its 7-methyl derivative (14) showed similar (13) or higher (14) A2A affinity than 11a and 11b but showed no (13) or only a low degree (14) of selectivity versus A1-, A2B-, and A3-AR. The A2A-selective sulfostyryl-DMPX derivatives exhibit high water-solubility and may be useful research tools for in vivo studies.

A series of 8-substituted derivatives of 3,7-dimethyl-1-propargylxanthine (DMPX) was synthesized and investigated as A2A adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored. A recently developed synthetic procedure starting from 3-propargyl-5,6-diaminouracil proved to be the method of choice for the preparation of this type of xanthine derivatives. The novel compounds were investigated in radioligand binding studies at the high-affinity adenosine receptor subtypes A1 and A2A and compared with standard A2A adenosine receptor antagonists. Structure-activity relationships were analyzed in detail. 8-Styryl-substituted DMPX derivatives were identified that exhibit high affinity and selectivity for A2A adenosine receptors, including 8-(m-chlorostyryl)-DMPX (CS-DMPX, Ki A2A = 13 nM, 100-fold selective), 8-(m-bromostyryl)-DMPX (BS-DMPX, Ki A2A = 8 nM, 146-fold selective), and 8-(3,4-dimethoxystyryl)-DMPX (Ki A2A = 15 nM, 167-fold selective). These and other novel compounds are superior to the standard A2A adenosine receptor antagonists KF17837 (4) and CSC (5) with respect to A2A affinity and/or selectivity.

Summary Configurationally stable analogs of the potent, A 2A -selective adenosine receptor (AR) antagonist 3, 7-dimethyl-1-propargyl-8-styrylxanthine (8-styryl-DMPX, 3) were synthesized and investigated in radioligand binding assays for affinity to the high-affinity A 1 - and A 2A -AR subtypes of rat brain. All derivatives prepared, including compounds in which the styryl double bond was replaced by a cyclopropane ring or a triple bond, or in which it was integrated into a (hetero) cyclic ring system, were less potent and less selective compared to the parent compound 3. The best compound of the present series was 8-(phenylethynyl)-DMPX ( 21 ), exhibiting a K 1 value at A 2A -AR of 300 nM and a > 10-fold selectivity versus A 1 -AR. In view of its configurational stability, 21 may be an interesting lead compound for the development of more potent A 2A antagonists by introducing appropriate substituents in the phenyl ring. Based on conformational analysis of 8-styrylxanthine and 8-(2-naphthyl)xanthine derivatives, it is hypothesized that the bioactive conformation of ( E )-8-styryl substituents with regard to the imidazole ring of the xanthine nucleus at A 2A -AR may be nearly coplanar and cis oid, and may differ from the bioactive conformation of such xanthine derivatives at A 1 -AR.

In the present study we synthesized aza-analogs of 8-styrylxanthines, in which the ethenyl bridge is replaced by an imine, amide, or azo function, in order to investigate structure-activity relation-ships of the 8-substituent of A 2A -selective xanthine derivatives. Thus, various 8-substituents were combined with theophylline or caffeine, respectively, and affinities of the novel compounds for adenosine A 1 - and A 2A -receptors were determined and compared with those of analogous 8-stytylxanthine derivatives. 8-(Benzylideneamino)caffeine derivatives exhibited high affinity and selectivity for A 2A -adenosine receptors, but were unstable in aqueous buffer solution at physiological pH values. 8-(Phenylazo)caffeine derivatives were less potent than corresponding 8-styrylcaffeine derivatives at adenosine receptors. The most potent azo compound of the present series was 8-(m-chlorophenylazo)caffeine (14b) exhibiting a K i value of 400 nM a A 2A -adenosine receptors and 20-fold selectivity versus A 1 -receptors. Due to the facile synthetic access to 8-(phenylazo)xanthine derivatives, which are obtained by coupling of 8-unsubstituted xanthines, with phenyldiazonium salts, 14b may be an interesting new lead compound for the development of more potent and selective A 2A -antagonists with azo structure.

A series of 33 novel, mostly chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives has been synthesized and investigated in radioligand binding assays at the high-affinity adenosine receptor (AR) subtypes A1 and A2a. The compounds can be envisaged as adenine and hypoxanthine analogs lacking the nitrogen in the 7-position (7-deazaadenines and 7-deazahypoxanthines). 7-Deazaadenines were much more potent than 7-deazahypoxanthines at AR with A1AR affinities in the low-nanomolar range, extraordinarily high selectivity for the rat brain A1AR versus the A2aAR (several thousandfold), and high stereoselectivity (up to 96-fold). Pyrimido[4,5-b]indoles were more potent A1AR antagonists compared to pyrrolo[2,3-d]pyrimidines. Compound 34a (APEPI) is one of the most potent and most selective nonxanthine A1AR antagonists known to date (Ki = 2.8 nM, > 2000-fold A1-selective). A new class of very potent A1AR antagonists has been identified, namely, 2-phenyl-7-deazaadenines bearing a substituent at the exocyclic amino group (N4-substituted pyrrolo[2,3-d]pyrimidines). (R)-N- (1-Phenylethyl)-4-amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin e (DPEAP, 17a) showed a Ki value of 6.7 nM at A1AR and > 4000-fold A1 selectivity. Different binding modes are postulated for the N4-substituted 4-aminopyrrolo[2,3-d]pyrimidines (e.g., 17a) and the 7-substituted derivatives (e.g., 1a), based on a comparison of steric, electronic, and hydrophobic properties of the two classes of compounds. Water solubility and lipophilicity have been determined for selected compounds. 4-Amino-5,6-dimethyl-2-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (4a) showed the highest water solubility/A1AR affinity ratio of 368 in the present series, over 2000-fold A1 selectivity, and 64-fold stereoselectivity (R > S). Therefore, 4a should be an interesting compound for in vivo evaluation.

A series of arylidene imidazo[2,1-b]thiazoles was synthesized, in order to investigate the influence of different spatial arrangements of the arylidene substituent towards the bicyclic structure of imidazo[2,1-b]-thiazole on benzodiazepine receptor affinity. 1,2- And 2,3-cyclized derivatives of mono- and di-substituted Z-5-arylidene-2-thiohydantoins were investigated. As an example of E isomers E-5-benzylidene-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one was obtained. The spatial arrangement of the arylidene sub stituent toward the bicyclic structure as well as the character of isomers had little influence on the benzo diazepine receptor affinity of the compounds. It seems that the greatest influence on biological activity has the nature and the number of substituents on the phenyl ring. All investigated imidazo[2,1-b]thiazoles were less active than previously described arylidene imidazo[2,1-b]thiazepinones.