Ivo Monkovic

Dihydropyridine neuropeptide Y Y1 receptor antagonists

Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).

Novel quinolizidine salicylamide influenza fusion inhibitors

A novel series of quinolizidine salicylamides was synthesized as specific inhibitors of the H1 subtype of influenza A viruses. These inhibitors inhibit the pH-induced fusion process, thereby blocking viral entry into host cells. Compound 16 was the most active inhibitor in this series with an EC50 of 0.25 microg/mL in plaque reduction assay. The synthesis and the SAR of these compounds are discussed.

Potential non-dopaminergic gastrointestinal prokinetic agents in the series of substituted benzamides

Abstract A series of 2-substituted-4-amino-5-chloro-N-[2-diethylaminoethyl]benzamides was synthesized and evaluated for gastrointestinal motility enhancing activity in vitro (enhancement of field stimulated guinea pig ileum test) and in vivo (enhancement of rat stomach emptying). A number of compounds were shown to be potent gastrointestinal prokinetic agents yet were devoid of dopaminergic D2-receptor antagonism as shown by their inability to displace [3H]spiperone from brain membranes. The model compound 6b would be expected to have clinical use in a spectrum of upper gastroinstestinal motility disorders but without the central nervous system side effects characteristic of dopaminergic D2-receptor blockade in the brain.

Synthetic Morphinans and Hasubanans. Part IV. Total Synthesis of 3,14-Dihydroxyisomorphinans, 3-Methoxy-Δ8,14-morphinans, and 9α-Hydroxy-3-methoxyhasubanan

The synthesis of a versatile intermediate 4a-(2-aminoethyl)-l,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (3a) and its utilization in the synthesis of 9α-hydroxy-3-methoxy-17-methylhasubanan (10), 3,14-dimethoxy-17-methylisomorphinan (9l), various 14-hydroxyisomorphinans (9), and 3-methoxy-Δ8,14-morphinan (11b) is described. A number of 17-alkyl-3,14-dihydroxyisomorphinans were prepared and tested for narcotic antagonist and analgesic activities in laboratory animals. Some of these new compounds have exhibited significant activities.

Use of 2-oxazolidinones as latent aziridine equivalents. III. Preparation of N-substituted piperazines

Abstract A number of N-aryl and N-alkyl substituted piperazines 1 were prepared from variously substituted 2-oxazolidinone derivatives 3. The method involved treatment of 3 with HBr in glacial acetic acid followed by heating the resulting ring-opened salts 5 in alcoholic solvent. The piperazines 1a–1q were isolated by crystallization in yields ranging from 23–91%.

Total synthesis of 3,14-dihydroxyisomophinans and 9α-hydroxy-3-methoxyhasubanans

Total synthesis of 3,14-dihydroxyisomorphinans and 9α-hydroxy-3-methoxyhasubanans via 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (Ia) is described.

Chapter 12. Gastrointestinal Motility Enhancing Agents

Publisher Summary This chapter discusses the therapeutic use of the prokinetic compounds in treating some gastrointestinal motor disorders. A brief outline on the neuroanatomical organization of the gastrointestinal tract and on the methods employed to study motility and its disorders is also discussed in this chapter. Motility is a dynamic term and consists of two distinct components, the movement of the gut wall and the movement of ingesta through the gastrointestinal tract. Different parts of the gastrointestinal tract have diverse functions, and hence the motility of each organ is different. Acetylcholine is an excitatory neurotransmitter and in the gastrointestinal tract evokes contractions. Other muscarinic agonists, such as bethanechol, methacholine, or carbachol also increase intestinal motility. Drugs that are cholinesterase inhibitors act as muscarinic agonists, enhancing the effect of released acetylcholine by inhibiting its degradation. Since its introduction, metoclopramide has been used therapeutically to accelerate bowel transit in fluoroscopic examinations to facilitate tube placement into the small bowel, to relieve diabetic gastroparesis, and to treat gastroesophageal reflux. In clinical studies, it has been demonstrated that bromopride increases esophageal motility and accelerates small bowel transit. The role of peptides in gastrointestinal motility is becoming very important because various peptides have been localized immunocytochemically and their role as neurotransmitters or neuromodulators is becoming apparent. The influence of a particular peptide on gut motility may be different in vivo and in vitro . Several peptides, such as vasoactive intestinal peptide, secretin, and glucagon influence gastrointestinal motility by inhibiting or relaxing smooth muscle. However, there is a need to synthesize and identify prokinetic compounds that will enhance gastrointestinal motility and be devoid of the side effects. This goal can be achieved only when further advances are made in the understanding of the physiology and pharmacology of gastrointestinal motility.