A. Michael Crider

Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores.

Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(alpha-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the alpha-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50=5.8 mgkg(-1), TD50 =36.4 mgkg(-1), PI=6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.

Synthesis and Evaluation of Morpholinoalkyl Ester Prodrugs of Indomethacin and Naproxen

Morpholinoalkyl esters (HC1 salts) of naproxen 1 and indomethacin 3 were synthesized and evaluated in vitro and in vivo for their potential use as prodrugs for oral delivery. Prodrugs were freely soluble in simulated gastric fluid (SGF) and pH 7.4 phosphate buffer and showed a minimum of a 2000-fold increase in solubility over the parent drugs. All prodrugs were more lipophilic than parent drugs as indicated by n-octanol/pH 7.4 buffer partition coefficients but less lipophilic in terms of n-octanol/SGF partition coefficients. Potentiometrically determined pKas for prodrugs were in the range of 6.89 to 8.62 at 25°C. All prodrugs were quantitatively hydrolyzed to their respective parent drugs by enzymatic and/or by chemical means. An increase in carbon chain length rendered the prodrugs more stable at pH 7.4 but less stable in SGF. The esters were generally found to be hydrolyzed rapidly in rat plasma at 37°C, the half-lives being in the range of 1.2–31.0 min. Based on in vitro results, prodrugs 2c and 4c were chosen to evaluate solid-state stability, in vivo bioavailability, and ulcerogenicity. At elevated temperatures, the solid-state decomposition of 2c and 4c followed biphasic kinetics, with rapid decomposition occurring initially. The prodrugs were 30–36% more bioavailable orally than the parent drugs following a single equimolar solution dose in rats. Prodrugs 2c and 4c were significantly less irritating to gastric mucosa than parent drugs following single-dose and chronic oral administration in rats.

cis- and trans-2,3,3a,4,5,9b-Hexahydro-1H-benz[e]indoles: synthesis and evaluation of dopamine D2 and D3 receptor binding affinity

Abstract cis- and trans-2,3,3a,4,5,9b-Hexahydro-1H-benz[e]indoles were synthesized as conformationally rigid analogues of 3-phenylpyrrolidine and evaluated for dopamine (DA) D2S and D3 receptor binding affinity. The tricyclic benz[e]indole nucleus was constructed by a previously reported reductive amination-cyclization procedure. Several unexpected side products were isolated and characterized using the general method. The trans-diastereoisomers exhibited greater affinities for the DA D3 receptor than the corresponding cis-isomers. In both the cis- and trans- series the greatest affinity for DA D3 receptors was shown by compounds substituted with N-n-propyl or N-allyl groups. The cis-(±)-N-allyl derivative 21e demonstrated a D2S/D3 selectivity of 290. Resolution of cis-(±)-5 and trans-(±)-21c into individual enantiomers showed that in both series the more active isomer had 3aR absolute configuration. These novel ligands may be useful tools for gaining additional information about the DA D3 receptor.

Somatostatin receptor agonists and antagonists

Somatostatin is a cyclic peptide that is widely distributed in the CNS, the periphery and in a variety of tumours. Two biologically active forms, somatotropin release-inhibiting factor (SRIF)-14 and SRIF-28, exert their effects through activation of five G-protein-coupled receptor subtypes (sst1 – sst5). These peptides act as neurotransmitters or hormones and inhibit the secretion of other peptides, such as insulin, growth hormone and glucagon. Metabolically stable peptide and structurally diverse non-peptide analogues have been developed as subtype-selective agonists and antagonists. The availability of these novel SRIF analogues will greatly facilitate our understanding of the function and role of specific SRIF receptors. SRIF analogues offer therapeutic potential in the regulation of hormone secretion, diseases of the CNS and periphery and in the treatment and diagnosis of various tumours. This review will focus on an overview of SRIF, new developments related to SRIF role and function and the discovery of novel peptide and non-peptide agonists and antagonists.