Synthesis and pharmacological characterisation of a conformationally restrained series of indole-2-carboxylates as in vivo potent glycine antagonists.

After the identification of GV150526, the indole-2-carboxylate template was further explored in order to identify novel potential anti-stroke agents. In particular, the SAR of the side chain present at the C-3 position of the indole nucleus was widely studied. In this paper, the synthesis and the pharmacological profile of a further class of conformationally restricted analogues of GV150526 as in vitro and in vivo potent glycine antagonists is reported. In particular, a pyrazolidinone derivative was identified as a potent neuroprotective agent in animal models of cerebral ischaemia.

N-phenylalkyl-substituted tropane analogs of boat conformation with high selectivity for the dopamine versus serotonin transporter.

A series of N-phenylalkyl-substituted tropane analogs of boat conformation was synthesized, and these tropanes were evaluated for their ability to inhibit high affinity uptake of dopamine (DA) and serotonin (5-HT) into striatal nerve endings (synaptosomes). Some of these compounds exhibit high affinity for the DA transporter with a 5-HT/DA transporter selectivity ratio of >50.

Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents.

Thyrotropin-releasing hormone (TRH) and certain TRH analogs show substantial neuroprotective effects in experimental brain or spinal cord trauma but also have other physiological actions (autonomic, analeptic, and endocrine) that may be undesirable for the treatment of neurotrauma in humans. We developed a novel TRH analog (2-ARA-53a), with substitutions at the NH(2)-terminus and imidazole ring, that preserves the neuroprotective action of TRH-like compounds while decreasing or eliminating their autonomic, analeptic, and endocrine effects. Rats administered 2-ARA-53a (1.0 mg/kg, n = 17) intravenously 30 min after lateral fluid percussion brain injury showed marked improvement in motor recovery compared with vehicle-treated controls (n = 14). Treatment of mice subjected to moderate controlled cortical impact brain injury, at the same dose and time after trauma (n = 8), improved both motor recovery and cognitive performance in a water maze place learning task compared with vehicle-treated controls (n = 8). In injured rats, no autonomic or analeptic effects were observed with this compound, and endocrine effects were significantly reduced with 2-ARA-53a, in contrast to those found with a typical NH(2)-terminal-substituted TRH analog (YM-14673). These findings demonstrate that the neuroprotective effects of TRH-related compounds can be dissociated from their other major physiological actions and suggest a potential role for dual-substituted TRH analogs in the treatment of clinical neurotrauma.

1-amino-APDC, a partial agonist of group II metabotropic glutamate receptors with neuroprotective properties.

The synthesis of the 1-amino derivative of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid (1-amino-APDC), a selective metabotropic glutamate ligand, is disclosed. This compound acts as a partial agonist of the group II mGluRs and shows pronounced neuroprotective properties in the NMDA model of cell toxicity.

Synthesis and biological properties of new 2beta-alkyl- and 2beta-aryl-3-(substituted phenyl)tropane derivatives: stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters.

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, we have been involved in efforts to further elucidate the nature of cocaine's binding to the dopamine transporter (DAT) through strategic modifications of its structure. In the case of the substituent located at the 2-position of the tropane ring, studies have revealed the ability of the transporter to accommodate groups of diverse structure, including ester, ketone, alkyl, alkenyl, heterocyclic, and aryl substituents, without loss of DAT binding affinity. In the present study, we report our results pertaining to the ability of the DAT to accommodate the WIN-type structures possessing alkyl or aryl groups at the 2-position and which adopt either a chair or a boat conformation of the tropane ring. Moreover, we discuss the influence of the stereochemistry of these compounds in their selectivity for the DAT versus the serotonin transporter (5HTT). Additionally, we point out the importance of using Ki values rather than IC50 values when making such comparisons of transporter selectivity. One of the most interesting compounds identified in the present work is a 2, 3-diaryltropane 22 in a boat conformation that is highly selective (69-fold) for the DAT over the 5HTT. The ability to prepare this compound as well as related structures by our oxidopyridinium betaine-based dipolar cycloaddition strategy further underscores the versatility of this particular chemical approach to the preparation of diverse tropane analogues. The use of the optically pure olefin p-tolyl vinyl sulfoxide as the dipolarophile in this reaction allows access to these novel tropanes in nonracemic form.

Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton.

To discover agents that might be useful in the treatment of cocaine abuse, we have chosen to re-explore a class of molecules that was first reported by Clarke et al. in 1973 and that was and shown to lack locomotor stimulatory activity in mice. These compounds are piperidine-3-carboxylic acid esters bearing a 4-chlorophenyl group in position 4, and as such, these structures may be viewed as truncated versions of the WIN series compounds, i.e., they lack the two-carbon bridge of the tropanes. All members of this class were synthesized starting from arecoline hydrobromide and obtained in optically pure form through resolution methods using either (+)- or (-)-dibenzoyltartaric acid. Interestingly, we have found that these piperidines do, in fact, exhibit substantial affinity in both WIN 35, 428 binding at the dopamine transporter and in the inhibition of [3H]dopamine uptake. Of all of the compounds synthesized, the 3-n-propyl derivative (-)-9 was found to be the most potent with a binding affinity of 3 nM. This simple piperidine is thus 33-fold more potent than cocaine in binding affinity and 29-fold more potent in its inhibition of dopamine uptake. Although no efforts have presently been made to "optimize" binding affinity at the DAT, the substantive activity found for the n-propyl derivative (-)-9 is remarkable; the compound is only about 10-fold less active than the best of the high-affinity tropanes of the WIN series. As a further point of interest, it was found that the cis-disubstituted piperidine (-)-3 is only about 2-fold more potent than its trans isomer (+)-11. This result stands in sharp contrast to the data reported for the tropane series, for the epimerization of the substituent at C-2 from beta to alpha has been reported to result in a lowering of activity by 30-200-fold. This smaller spread in binding affinities for the piperidines may reflect the smaller size of these molecules relative to the tropanes, which allows both the cis and the trans isomers to adjust themselves to the binding site on the DAT. Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken together with their reported lack of locomotor activity, provides a compelling argument for exploring this class of molecules further in animal behavioral experiments. The present work thus broadens the scope of structures that may be considered as lead structures in the search for cocaine abuse medications.

Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist.

To better characterize the roles of metabotropic glutamate receptors (mGluRs) in physiological and pathophysiological processes, there is an important need to learn more about the structural features relevant to the design of novel, high-affinity ligands that are family and subtype specific. To date, many of the biological studies that have been conducted in the area of mGluR research have made use of the agonist (1S,3R)-ACPD. This compound has been shown to act as an agonist at both the group I and group II receptors while showing little selectivity among the four subtypes belonging to these two groups. Moreover, (1S,3S)-ACPD, the cis isomer, shows negligible activity at group I receptors and is a good agonist of mGluR2. Since ACPD is itself somewhat flexible, with four distinctive conformations being identified from molecular modeling studies for the trans isomer and five conformations for the cis isomer, we believed that it would be of interest to examine the activity of an ACPD analogue that has been constrained through the introduction of a single carbon atom bridge. Accordingly, we have prepared an aminobicyclo[2.1.1]hexanedicarboxylic acid (ABHxD-I) analogue of ACPD. The synthesis of this compound was accomplished by use of an intramolecular [2 + 2] photocycloaddition reaction, in which four distinct isomers were isolated. Of these four compounds, only a single isomer, ABHxD-I (6a), was found to be a potent agonist of the mGluRs. This compound, which expresses the fully extended glutamate conformation, was found to be more potent than ACPD at all six of the eight mGluR subtypes that were investigated and to be comparable to or more potent than the endogenous ligand, glutamate, for these receptors. Interestingly, despite its fixed conformation, ABHxD-I, like glutamate, shows little subtype selectivity. Through modeling studies of ABHxD-I (6a), ABHD-VI, LY354740, (1S,3R)-ACPD, (1S, 3S)-ACPD, and l-glutamate, we conclude that the aa conformation of l-glutamate is the active conformation for both group I and group II mGluRs. Moreover, the modeling-based comparisons of these ligands suggest that the selectivity exhibited by LY354740 between the group I and group II mGluRs is not a consequence of different conformations of L-glutamate being required for recognition at these mGluRs but rather is related to certain structural elements within certain regions having a very different impact on the group I and group II mGluR activity. The enhanced potency of ABHxD-I relative to trans-ACPD commends it as a useful starting point in the design of subtype selective mGluR ligands.

Diastereomeric separation of 1,5-benzodiazepines due to the presence of a chiral centre on the N-5 alkylic chain.

The presence of a chain bearing a stereogenic centre at the N-5 position of 1-(1-adamantylmethyl)-3-arylureido-2,4-dioxo-1,5-benzodiazep ines induces optical resolution. The synthesis of these compounds and their potency as potential CCK-B receptor antagonists is discussed briefly here.

Synthesis and metabotropic glutamate receptor activity of a 2-aminobicyclo[3.2.0]heptane-2,5-dicarboxylic acid, a molecule possessing an extended glutamate conformation.

A photochemical approach to the synthesis of the aminobicycloheptane 6a is reported. This compound assumes an extended glutamate conformation, and for this reason was created to further probe the structural features relevant to achieving selectivity for the subtypes of the metabotropic glutamate family of receptors.

Synthesis of 5-membered ring-type compounds as potential cholecystokinin receptor ligands.

Imidazolidine-2,4-diones and 1,5-diphenyl tetramic acid derivatives were selected in order to evaluate some 5-membered heterocyclic ring compounds as potential templates for the synthesis of CCK receptor ligands. All the compounds were evaluated in vitro towards both CCK-B and CCK-A receptors.

Synthesis and receptor binding affinity of cholecystokinin receptor ligands: 2-and 1-indolyl derivatives of PD134308.

The synthesis of two "dipeptoids" structurally related to the CCK-B antagonist CI-988 (PD134308) is described. The 2- and 1-indolyl derivatives 4a, b were prepared in order to define the role of the tryptophan moiety in this series of "dipeptoids". They were evaluated as competitors in the binding of [3H]-CCK8S on guinea pig brain CCK-B receptors.