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Amino acid derived spirocyclic 2,6-dioxopiperazines are easily and regioselectively opened by base-promoted nucleophilic attack of hydroxide or H2O on the less crowded carbonyl group at C-6 to give N-(1-carbamoylcyclohexyl)amino acid derivatives. However, the imide group of the 2,6-dioxopiperazine ring is rather unreactive toward alcohols, alkoxides, and amines.

This review covers our studies on the highly stereoselective synthesis of indole alkaloid analogues containing the novel tetraheterocyclic ring system 1,2,4,5,10b,10c-hexahydropyrrolo[1',2',3':1,9a,9]-imidazo[1,2-a]indole by acid-mediated domino cyclative electrophile additions upon tryptophan-derived a-amino nitriles. When the electrophile is a proton, a tautomerization takes place to give 10b unsubstitutedhexahydropyrrolo[ 1',2',3':1,9a,9]imidazo[1,2-a]indoles, while, the acid-mediated reaction with other electrophiles, such as halosuccinidides, prenyl bromide, the Corey-Kim reagent, or oxidants, leads to 10b-substituted analogues. This reaction requires the acid-mediated activation of the cyano group, which is transformed in an endocyclic amidine. Further manipulation of the 10b-halo- or 10b-methylthiomethyl groups allows to extend the diversity of substituents at this position. The endocyclic amidine can be N-acetylated and N-benzyloxycarbonyl-protected, but not N-tert-butoxycarbonyl-protected. Finally, the alkylative hydrolysis of the amidine leads to the corresponding lactam analogues.

A suitable solid-phase approach, based on Fmoc/tBu methodology and on the use of 2-chlorotrityl resin, allowed a rapid and efficient preparation of new GPE analogues. Most of the synthesized tripeptides displayed glutamate receptor binding affinity comparable to that of GPE, but only a few derivatives showed significant neuroprotective activity.

The influence of several modifications on the GPE tripeptide structure upon the binding to GluRs and on their neuroprotective effects has been studied. The results indicated that the prevention of neuronal death showed by GPE and some analogues is not directly related to their affinity at glutamate receptors.

A rational combination of site-directed mutagenesis studies, structure−activity relationships, and dynamic-based docking of pyridopyrimidine-derived CCK1R antagonists into a refined three-dimensional model of the CCK1R allowed us to identify the receptor residues and the ligand functional groups implicated in the molecular recognition process. Our results provided unambiguous evidence that the binding site of these antagonists is overlapping that of the C-terminal tetrapeptide of CCK. In particular, Asn333 and Arg336 residues of the CCK1R are essential for high-affinity binding of these ligands. Moreover, the 2-aryl group in the pyridopyrimidine derivatives shares the same binding pocket as the C-terminal Phe side chain of CCK. Our [pyridopyrimidine·CCK1R] complex model is consistent with previous suggestions concerning the molecular basis that governs functional activity and provides useful considerations about the high CCK1 versus CCK2 selectivity of our derivatives and could contribute to fine-tune the rational design of new molecules with optimized properties.

With the aim of reversing selectivity or antagonist/agonist functionality in the 5-(tryptophylamino)-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-derived potent and highly selective CCK1 antagonists, a series of 4-benzyl and 4-methyl derivatives have been synthesized. Whereas the introduction of the benzyl group led, in all cases, to complete loss of the binding affinity, the incorporation of the methyl group gave a different result depending on the stereochemistry of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold. Thus, the introduction of the methyl group into the (4aS,5R)-diastereoisomers, giving a (4S)-configuration, produced a 3-fold increase in the CCK1 binding potency and selectivity. However, the same structural manipulation in the opposite (4aR,5S)-stereochemistry, leading to a (4R,4aR,5S)-configuration, produced reversal of the selectivity for CCK1 to the CCK2 receptors. The replacement of the Boc group at the tryptophan moiety by a 2-adamantyloxycarbonyl group also contributed to that reversal. The resulting compounds displayed moderate CCK2 antagonist activity in rat and human receptors, and a very small partial agonist effect on the production of inositol phosphate in COS-7 cells transfected with the wild-type human CCK2 receptor.

The synthesis of branched peptides from cyanomethylenamino pseudopeptides, via catalytic hydrogenation in the presence of amino acid derivatives, is described. When the inserted amino acid was a glycine derivative, the resulting branched peptide lactamized in situ to 2-oxopiperazine derivatives. This new C-backbone peptide branching approach is compatible with the diversity of amino acid side chains.

To further define the pharmacophore of the potent and selective 5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based CCK1 receptor antagonists the electronic and topographic properties of the central 1,3-dioxoperhydro-pyrido[1,2-c]pyrimidine scaffold have been modified. With this aim, the 1- and 3-oxo groups have been replaced by the thioxo- and deoxi-analogues, and the fused piperidine ring has been contracted to the corresponding pyrrolidine moiety. The results of the evaluation of the new analogues as CCK receptor ligands, in rat pancreas and cerebral cortex preparations, showed that, whereas replacement of oxygen with sulfur is allowed, reduction of the 1- or 3-oxo groups or the contraction of the fused piperidine ring lead to the complete loss of binding affinity at CCK1 receptors. The thioxo-analogues 5a, 8a, 12a, and 12b showed functional CCK1 antagonist activity, inhibiting the CCK-8-stimulated amylase release from pancreatic acinar cells. The 1-thioxo analogue 5a, with subnanomolar affinity (IC50 = 0.09 × 10-9 M), was found to be the most potent and selective compound within the family of 5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based CCK1 antagonists.

To establish structure−activity relationships a new series of analogues of the highly potent and selective CCK1 receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]-pyrimidine (1a) modified at N2-position of the central scaffold has been prepared and evaluated as CCK receptor ligands. With this aim the N2-benzyl group has been replaced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2-phenylethyl group. Then, substituents with different electronic and steric properties were introduced into different positions of the phenyl group of analogues 19a and 19b. The results of the CCK receptor binding and in vitro functional activity evaluation suggest the importance of the lipophilic character and an appropriate spatial orientation of the moiety linked at the N2-position of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine template for potent and selective binding and antagonist activity at CCK1 receptor subtype. The 2-cyclohexyl and (2S)-1-naphthyl derivatives 18a and (2S)-20a have emerged as more potent and selective CCK1 receptor antagonists than the lead compound 1a. Additionally, the results confirm the (4aS,5R)-stereochemistry at the central bicyclic skeleton as an essential structural requirement for potent binding to this receptor subtype.

Analogues of the previously reported potent and highly selective CCK1 receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK1 receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3,3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK1 receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.

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In order to find new classes of non-peptide cholecystokinin (CCK) ligands, the conformational restriction of a series of weak 3-oxoindolizidine-based CCK antagonists has been both decreased and increased. This tactic yielded a series of monocyclic 2-oxopyrrolidine derivatives 4 with selectively for CCK-A or CCK-B receptors and with slightly improved binding affinity at the CCK-A receptor subtype with respect to the model 3-oxoindolizidines. In contrast, the incorporation o the Trp residue at the secondary amino group of a pyrrolo[1, 2-a]pyrazine template 5, involving a drastic restriction in the conformational flexibility of the molecule, resulted in a series of bicyclic derivatives that did not bind to CCK receptors at concentrations up to 10-5 M.

The synthesis and stereochemical structure-activity relationships of a new class of potent and selective non-peptide cholecystokinin-A (CCK-A) receptor antagonists based on the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine skeleton are described. The most potent member of this series of eight diastereoisomers, (4aS,5R)-2-benzyl-5-[N-[(tert-butoxycarbonyl)-L- tryptophyl]-amino]-1,3-dioxoperhydropyrido[1,2-c]pyrimidine, displays nanomolar CCK-A receptor affinity and higher than 8000-fold potency at the CCK-A than at the CCK-B receptor. As CCK-A antagonist, this compound inhibits the CCK-8-evoked amylase release from pancreatic acinar cells at a low concentration, similar to that of the typical antagonist Devazepide. Highly strict stereochemical requirements for CCK-A receptor binding and selectivity have been found. The L-Trp and the 4a,5-trans disposition of the bicyclic perhydropyrido[1,2-c]pyrimidine are essential for binding potency and selectivity.

A series of CCK-4 restricted analogues, incorporating a 3-oxoindolizidine bicyclic lactam as conformational constraint, is described. The 8-(Boc-tryptophyl)amino-2-benzyl derivatives behave as weak CCK-A or CCK-B receptor antagonists. The main factors for selectivity are the configuration at C-2 position of the 3-oxoindolizidine ring and at the Trp residue.

Catalytic hydrogenation of cyanomethyleneamino pseudopeptides, followed by peptide coupling and cyclization of the resulting aminomethyleneamino intermediates, gives access to branched and conformationally constrained peptide analogues.

The synthesis of new 8-tert-bytyloxycarbonylamino-3-oxoindolizidine-1-carboxylic acid esters with different stereochemistry at position 1, 8, and 8a is described. Three different paths from ornithine derivatives have been utilized. These compounds can be employed as new templates in synthetic analogues of bioactive peptides. Starting from ornithine derivatives, three different synthetic methods for the preparation of the title compounds with different stereochemistry at positions 1, 8, and 8a are described.

The reaction sequence that converts Boc-L- or Boc-D-Orn(Z)-OH into 8-amino-3-oxoindolizidine-2-carboxylate derivatives has been examined, in order to determine the step during which partial racemization occurs. By using chiral derivatizating agents, it has been demonstrated that the temperature-dependent racemization takes place during the intramolecular reductive amination process, involved in the elaboration of the indolizidine ring by hydrogenation of the corresponding 4-keto diester derived from ornithine. It was shown from deuterium labelling experiments that this process proceeds through an equilibrium between imine–enamine intermediates which also accounts for the high stereoselectivity in the generation of the C-8a centre of the indolizidine skeleton.

The synthesis of 4,7-di- and 4,7,7-trisubstituted 3,6-dioxoperhydropyrrolo[1,2-a]pyrazine-7-carboxylale derivatives is described. The approach used for the preparation of this heterocyclic template is based on the reductive animation of 4-ketodiesters derived from dipeptides.

A general procedure for the preparation of (carbamoylmethylene)amino pseudopeptides from the corresponding (cyanomethylenene)amino analogues, compatible with peptide bonds and with the usual amino and carboxyl protecting groups, is described. This procedure involves the oxidative hydration of (cyanomethylene)amino pseudopeptides with basic hydrogen peroxide under phase-transfer conditions, using n-tetrabutylammonium hydrogen sulfate as catalyst. In the basic medium of this reaction the methyl esters of (carbamoylmethylene)amino pseudodipeptides cyclized to 2,6-dioxopiperazine analogues.