Fredric J. Vinick

CP-70,030 and CP-75,998: The first non-peptide antagonists of bombesin and gastrin releasing peptide

Abstract CP-70,030 and CP-75,998 were identified in a screening program as compounds able to displace [125I]-gastrin releasing peptide (GRP) from its rat brain receptor. We describe here the syntheses of these compounds and their characterization as bonafide GRP antagonists.

A superior synthesis of aspartame

Abstract The dipeptide sweetener, aspartame, has been prepared in high yield via the coupling of L-phenylalanine methyl ester and L-aspartic acid N-thiocarboxyanhydride.

Discriminative stimulus properties of phencyclidine (PCP)-related compounds: Correlations with 3H-PCP binding potency measured autoradiographically

Several PCP analogs, the putative PCP agonist MDP, and the sigma receptor agonists SKF-10,047 and dexoxadrol were tested for their ability to substitute for PCP in animals trained to discriminate PCP from saline. The potencies of these compounds in substituting for PCP in the behavioral task correlated with their abilities to inhibit the specific binding of 3H-PCP to rat hippocampal sections measured autoradiographically, which occurred at a single class of sites with an affinity of 85 nM and a capacity of 2646 fmol/mg protein. In addition to this specific binding, an additional nonspecific but displaceable fraction of total 3H-PCP binding was present. These results suggest that the specific 3H-PCP binding site measured in the hippocampus may be the type of binding site which mediates the behavioral effects of PCP and related compounds. Therefore, measurement of the inhibition of 3H-PCP binding at this site might aid in the search for PCP antagonists.

Chapter 5. Adaptive Changes in Central Nervous System Receptor Systems

Publisher Summary This chapter discusses the recent literature on adaptive changes in central norepinephrine (NE), serotonin (5-HT), and dopamine (DA) receptor systems and concentrates on the drug-induced effects that could relate to the therapeutic modes of action in human diseases. The chapter discusses the reviews of the topics associated with the central nervous system (CNS) receptor systems. A rapid and reversible desensitization and down-regulation of the β-receptors of rat cerebral cortex is observed on the incubation of tissue slices with isoproterenol or desipramine (DMI), an NE uptake blocker. Similar adaptive changes in the receptors of the NE system also occur in vivo in the brain when NE levels are altered. Depression is a CNS disease is believed to be associated with a perturbation of central NE transmission. The first effective drugs in depression were monoamine oxidase (MAO) inhibitors and tricyclic uptake blockers that increase the concentration of neuronal or synaptic NE, respectively. Administration of multiple daily doses of drug produces down-regulation faster than single daily dosing and allows a lower dose per injection. In a time course study in rats, DMI (10 mg/kg b.i.d.) elicited maximal desensitization of cyclic AMP (cAMP) accumulation by isoproterenol in cortical slices in 5 to 7 days and down-regulation of β-adrenoceptors in cortical membranes after seven days. The role of serotonergic changes in depression and anti-depressant therapy has been a subject of intense study. For example, brains of suicide victims exhibited an increase in cortical 5-HT 2 binding sites; either an increase or a decrease in 3 [H]imipramine binding.

A simple bis-annelation route to 3,4,5,6-tetrahydropyrido[3,2-c]quinolin-2-ones

Abstract A short, novel synthesis of the title ring system is described involving the intramolecular reaction of an amide dianion with a nitrile followed by in situ N-alkylation of the resultant intermediate.

Chapter 1. Atypical Antipsychotic Agents

Publisher Summary All neuroleptics currently approved in the United States produce extra-pyramidal side effects (EPS). The most common forms of EPS are parkinsonism, dystonia, akathisia, and tardive dyskinesia (TD). The first three types occur early in the course of neuroleptic treatment and can usually be ameliorated. The fourth form, TD, develops only after months or years of therapy. It can be life-threatening and is very difficult to reverse even after termination of neuroleptic treatment. Both acute and chronic EPS are believed to result from blockade of dopamine (DA) receptors in the neostriatum of the brain. The acute symptoms are likely because of a decrease in striatal DA functioning. On the other hand, TD appears to result from the ability of the striatal DA system to overcome the neuroleptic blockade and ultimately reestablish more normal levels of neurotransmission. Because the striatal DA receptors have been made supersensitive by chronic blockade, the restored dopaminergic stimulation produces the abnormal movements of TD. This chapter suggests putative mechanisms subserving a typical activity including selective antagonism of limbic DA receptors, antimuscarinic activity, gamma-arninobutyric acid (GABA) agonist activity, noradrenergic antagonist activity, serotonin (5-HT) entagonist activity and some other mechanisms. This chapter analyzes the mechanisms underlying clozapines unique and desirable clinical profile involving virtual absence of EPS with regard to the six putative rationales for atypical activity—selective antagonism of limbic DA receptors, antimuscarinic activity, GABA agonist activity, noradrenergic antagonist activity, 5-HT antagonist activity, and other mechanisms. The chapter discusses clinically tested putative atypical agents—fluperlapine, rimcazole, ritanserin, ritanserin—and some other putative atypical antipsychotics—BMY-14802, CGS-10746B, cinuperone, zmperozide, dapiprazole, mezilamine, MJ-73980-1, and tiasperone.

Chapter 1 Antipsychotic Agents

Publisher Summary The organic pathology underlying chronic schizophrenia, which remains a devastating mental disorder, has emerged as a major topic of discussion. It presents an extremely difficult challenge for the discovery of safe and effective therapeutics. Recent studies, employing positron emission tomography have provided clear evidence of dopamine (DA) receptor proliferation in untreated schizophrenics. This finding may be an important underpinning for the DA hypothesis of schizophrenia, especially in light of the fact that DA antagonists are still the only established pharmacotherapy for psychosis. Nevertheless, anti-psychotic medications leave much to be desired, in terms of both efficacy and side effect profile. Consequently, the search continues for DA antagonists with improved therapeutic ratios as well as novel agents that can attenuate dopaminergic neurotransmission without direct interaction at DA receptors. Neuroleptic drugs are effective against the florid symptoms of psychosis. The benzamide neuroleptics form a distinct class of drugs on the basis of two attributes— that is, structural commonality and selectivity for D 2 DA receptors. Substituted benzamides have exhibited varying propensities to induce extrapyramidal side effects (EPS). Such drugs, for example, metoclopramide, resembles with classical neuroleptics with regard to EPS liability, while remoxipride also being similar in efficacy to classical agents but causes less severe EPS. It is recently observed to be a very selective, low potency D 2 blocker in vitro . Remoxipride preferentially inhibits the binding of [ 3 H]spiperone to DA receptors in limbic regions(rat brain). Striatal DA receptors are blocked only to the extent of 60%, even at very high drug doses. Raclopride possesses very high affinity for D 2 receptors in vitro and binds preferentially to the striatum in the rat in vivo . While neuroleptic drugs are effective against the florid symptoms of psychosis, negative symptoms of schizophrenia, such as social withdrawal and cognitive decline, remain uncontrolled.

Novel in vitro and in vivo inhibitors of prolyl endopeptidase

Abstract Inhibition of prolyl endopeptidase by Z-cyclohexyl prolinal and Z-indolinyl prolinal occurs with slow, tight binding inhibition and K i values of 2 – 3 nM. In vivo enzyme inhibition is also observed with a half time for recovery of enzyme activity of 3 – 4 h. Inhibition of prolyl endopeptidase by Z-cyclohexyl prolinal and Z-indolinyl prolinal occurs with slow, tight binding inhibition and K i values of 2 – 3 nM. In vivo enzyme inhibition is also observed with a half time for recovery of enzyme activity of 3 – 4 h.

An efficient synthesis of 1-phenyl-1-piperidino-trans-4-methylcyclohexane: Unanticipated total stereoselectivity in the catalytic hydrogenation of an olefin

Abstract A superior synthesis of the title compound, 1-phenyl-1-piperidino-trans-4-methylcyclohexane, is reported. The key step, the catalytic hydrogenation of 1-phenyl-1-piperidino-4-methylenecyclohexane hydrochloride, proceeds with unusual stereospecificity via addition of hydrogen trans to the axial phenyl substituent.