Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists.

The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13).

New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists.

A series of new 1,8-naphthyridine and quinoline derivatives were synthesized and evaluated for their cannabinoid receptor affinity. In particular, compounds 2, 5, 11, and 13 showed a high CB(2) affinity and CB(2) versus CB(1) selectivity, in agreement with molecular modeling studies. Furthermore, compound 2 also exhibited in vivo antinociceptive effects.

Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists.

On the basis of docking studies carried out using the recently published cannabinoid receptor models,35 new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a Ki of 1.0 nM.

Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis.

Three-dimensional models of the CB1 and CB2 cannabinoid receptors were constructed by means of a molecular modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template, and taking into account the available site-directed mutagenesis data. The cannabinoid system was studied by means of docking techniques. An analysis of the interaction of WIN55212-2 with both receptors showed that CB2/CB1 selectivity is mainly determined by the interaction in the CB2 with the nonconserved residues S3.

1,8-Naphthyridin-4-one derivatives as new ligands of A2A adenosine receptors.

A series of 1,8-naphthyridine derivatives bearing various substituents in position 3, 4, and 7 of the heterocyclic nucleus have been synthesized and evaluated for their affinity at the bovine and human adenosine receptors. The new compounds were found to lack the affinity toward A(1)AR, whereas many of them are able to acquire an interesting affinity and selectivity for the A(2A)AR.

Study on affinity profile toward native human and bovine adenosine receptors of a series of 1,8-naphthyridine derivatives.

A new series of 1,8-naphthyridine derivatives (29-44 and 46-52) bearing various substituents in different positions on the heterocyclic nucleus were synthesized in order to analyze the effects produced on the affinity toward the bovine adenosine receptors. These derivatives represent an extension of our previous work on this class of compounds with high affinity toward A(1) adenosine receptors.(19) The results of radioligand binding assays indicate that a large number of the 1,8-naphthyridine derivatives proved to be A(1) selective, with a high affinity toward bovine adenosine receptors in the low nanomolar range, and one (29) in the subnanomolar range.

Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors.

Cannabinoid receptors have been studied extensively in view of their potential functional role in several physiological and pathological processes. For this reason, the search for new potent, selective ligands for subtype CB receptors, CB(1) and CB(2), is still of great importance, in order to investigate their role in various physiological functions. The present study describes the synthesis and the biological properties of a series of 1,8-naphthyridine derivatives, characterised by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or arylalkyl substituent in position 1.

Synthesis and beta-blocking activity of (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine: identification of beta 3-antagonists.

Drugs acting on beta(1)- and beta(2)-adrenergic receptors are widely used for the clinical management of a large number of cardiovascular and respiratory pathologies. In the last decade, the discovery of the third subtype of beta receptors, the beta(3)-adrenoceptor, gave a further pharmacological target for the development of new selective drugs. Initially, a potential therapeutic use of beta(3)-selective agents seemed to be restricted to agonists, for the treatment of metabolic diseases, such as obesity, non-insulin-dependent diabetes, urinary frequency and incontinence.

Synthesis of 3- or 4-phenyl-1,8-naphthyridine derivatives and evaluation of antimycobacterial and antimicrobial activity.

A series of 3- or 4-phenyl-1,8-naphthyridine derivatives variously substituted in the positions 2, 6 and 7 were synthesized and evaluated for in vitro evaluation for their antimycobacterial activity as part of a TAACF TB screening program under the direction of the US National Institute of Health, NIAID division. Several compounds showed an interesting activity when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H(37)Rv and in particular compounds 2a, 4a,d, 8a,d and 8i, exhibit a % inhibition from 91 to 99.

4-[6-(Dansylamino)hexylamino]-7-methyl-2-phenyl-1,8-naphthyridine as a new potential fluorescent probe for studying A1-adenosine receptor.

A new fluorescent ligand for adenosine receptors, obtained by the insertion of a dansylamino-moiety with a linear hexyl spacer in the N4 position of a 1,8-naphthyridine adenosine receptor ligand, proved to possess a high affinity and selectivity for the A1 receptor subtype.

Synthesis of variously substituted 1,8-naphthyridine derivatives and evaluation of their antimycobacterial activity.

A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial acquisition and coordinating facility (TAACF). Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H37Rv, showed an interesting activity with % inhibition in the range 38-96%.

Synthesis and evaluation of antihypertensive activity of 1,8-naphthyridine derivatives. Part X.

A series of 4-(N-methylencycloalkylamino)-1,8-naphthyridine derivatives variously substituted in positions 2 and 7 were synthesized and pharmacologically investigated for possible antihypertensive activity. These compounds were tested to determine a possible vasodilator mechanism of action. Compounds 22, 23, 27-29, 47 and 48 showed satisfactory levels of potency (pIC(50)>5), which in one case (compound 23) reached a really interesting value (pIC(50) 6.

Synthesis and antiplatelet activity of some 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives.

Several 2,7-di(N-cycloamino)-3-phenyl-1,8-naphthyridine derivatives were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid, collagen and ADP. Only five compounds showed any appreciable activity, and the results of all the active derivatives were similar to those of papaverine in the test with arachidonic acid and collagen. Moreover, the most active compounds were investigated in the test with ADP and again showed a significant activity.

Synthesis and antiplatelet activity of some 3-phenyl-1,8-naphthyridine derivatives.

A series of 2-cycloalkylamino-3-phenyl-1,8-naphthyridine derivatives, variously substituted in the 6- and 7-positions were synthesized and tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonate, collagen and ADP. Compounds 5a,b, 7a,b, 8a and 10c,d showed a remarkable activity similar to that of indomethacin in the test with arachidonate and collagen. In the test with ADP only compound 8a showed a significant activity.

Synthesis and beta-blocking activity of (R,S)-(E)-oximeethers of 2, 3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2, 3-b]pyridine:potential antihypertensive agents - part IX.

The synthesis of oximeethers of 2,3-dihydro-1,8-naphthyridine and 2, 3-dihydrothiopyrano[2,3-b]pyridine is described. These compounds exhibit a selective beta-blocking activity, with a selectivity towards beta(2)-receptors. Groups in the N(1) position giving rise to a considerable steric hindrance led to a higher beta(2)-blocking selectivity, whereas groups creating a moderate hindrance caused a weak but significant decrease in beta(2)-antagonist potency.

A novel class of highly potent and selective A1 adenosine antagonists: structure-affinity profile of a series of 1,8-naphthyridine derivatives.

A series of 1,8-naphthyridine derivatives (12-36), bearing a phenyl group in position 2 and various substituents in positions 4 and 7, were synthesized in an attempt to obtain potent, selective antagonists for the A1 adenosine receptor subtype. The compounds were tested to evaluate their affinity for A1 compared with A2A and A3 adenosine receptor subtypes. In binding studies in bovine brain cortical membranes, most of the compounds showed an affinity for A1 receptors in the low nanomolar range and two in the subnanomolar range with an interesting degree of A1 versus A2A and A3 selectivity.

Synthesis and evaluation of antimycobacterial activity of 4-phenyl-1,8-naphthyridine derivatives.

Some 4-phenyl-1,8-naphthyridine derivatives with a piperazino group in the 2- and/or 7-position have been synthesized and evaluated for their tuberculostatic activity. The compounds 1, 6, 10, 17b,c and 19i showed a marked activity against Mycobacterium tuberculosis H37Rv. For this series of compounds, submitted to biological screening, no structure-activity relationship can be deduced.

Synthesis of some 4H-pyrido[1,2-a]pyrimidin-4-ones investigated as antimicrobial agents.

Synthesis of some 4H-pyrido[1,2-a]pyrimidin-4-ones and assay of their antibacterial and antifungal activity are reported. Compounds 3a-e,g were prepared by reaction of substituted 2-chloromethyl-4H-pyrido[1,2-a]pyrimidin-4-ones 2a-c with suitable amines. These compounds and the previously obtained analogues 5a-o and 6a,b have been tested for their antimicrobial activity.

Synthesis and local anesthetic activity of (E)- and (Z)-diethylaminoethyliminothers of 1,8-naphtyridine.

A series of (E)- and (Z)-diethylaminoethylimino ethers of 1.8-naphthyridine was prepared and characterized. Preliminary studies showed that none of the tested compounds presented noteworthy local anesthetic activity.

Study of inhibition of platelet aggregation of 1,8-naphthyridine derivatives.

The antiplatelet activity of some 1,8-naphthyridine derivatives was studied. The compounds displayed different abilities in blocking the effects of ADP, collagen and arachidonic acid. Four of them showed an in vitro remarkable activity similar to that of dipyridamole and papaverine.

Synthesis of pyrido[1,2-a]pyrimidin-4-ones. Potential antihypertensive agents. III.

Several 4H-pyrido[1,2-a]pyrimidine derivatives with a basic substituent in the 2-position have been synthesized. All the compounds tested showed no appreciable antihypertensive activity.

Synthesis of 1,8-naphthyridine derivatives. Potential antihypertensive agents. II.

Several 1,8-naphthyridine derivatives have been synthesized and pharmacologically investigated. Some of them exhibited a marked antihypertensive activity on spontaneously hypertensive rats.

Synthesis of new 6H-indolo[2,3-b] [1,8]naphthyridines and their specific inhibition of benzodiazepine receptor.

Some 3-amino- and 3-hydroxy-8-halosubstituted 6H-indolo[2,3-b] [1,8]naphthyridines were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. All prepared compounds were more active than the corresponding 8-unsubstituted derivatives. Moreover, among these compounds the 8-chloroindolonaphthyridines were clearly the most potent.

Synthesis and pharmacological activity of three new 9-aryl-8-azaadenine derivatives.

This paper describes the synthesis of three new 9-aryl-8-azaadenine derivatives (Ic, d, e) and of some related compounds, using the appropriate 1-substituted-5-amino triazoles (IV) as starting material. The new azaadenines were subjected to pharmacological screening and the carboxylic compound (I c) showed an interesting antiallergic activity, depending on the presence of the free acid function.

Synthesis and pharmacological activity of some 9-aryl-8-azapurine derivatives.

Because of the biological interest of 8-azaanologous of purine bases, the preparation of some 8-azapurines (IV) and (V), substituted in 9 position with aryl groups, is described. Compounds were obtained by closure of a pyrimidine nucleus on performed 5-amino-1,2,3-triazole derivatives. Some substances, subjected to pharmacological screening, showed an interesting antiallergic activity.