Joel G. Berger

SCH 57790: A novel M2 receptor selective antagonist

As a decrease in cholinergic neurons has been observed in Alzheimers Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.

Dopamine receptor binding properties of some 2,3,4,5-tetrahydro-1H-3-benzazepine-7-ols with non-aromatic substituents in the 5-position

Abstract 2,3,4,5-tetrahydro-1H-3-benzazepine-7-ols related to the selective dopamine D-1 antagonist SCH 23390, but bearing non-aromatic substituents in the 5-position possess considerable affinity and selectivity for D-1 vs. D-2 receptors.

Biochemical properties of D1 and D2 dopamine receptors.

The physiological action of dopamine are mediated by two distinct subtypes of receptors, D1 and D2 dopamine receptors. D1-receptors are linked to stimulation of adenylate cyclase whereas D2-receptors inhibit the enzyme and may also couple to other signal transduction systems such as ion channels. In order to characterize these receptors at the biochemical level we have developed specific probes for the identification and purification of these proteins. The ligand binding sites of the two receptors have been identified by photoaffinity labeling and reside on distinct polypeptides. In rat striatum, the D1 receptor binding site can be identified as a peptide of Mr = 72,000. In contrast, the D2 receptors appears to reside on an Mr = 94,000 peptide in most tissues. A larger peptide of Mr = 120,000 identified in the intermediate lobe of pituitary may represent the unproteolyzed form of this receptor. An affinity chromatography purification procedure has been developed for the D2 dopamine receptor. This procedure affords a substantial purification (greater than 1000 fold) of the receptor solubilized from bovine anterior pituitary glands with complete retention of its binding properties. These biochemical tools should eventually lead to the complete characterization of these two receptor subtypes.

Stereochemically complementary reductions of indoles

Abstract Indoles containing a 2, 3-fused bridged ring undergo highly stereoselective reduction to cis -fused derivatives with the endo - exo stereochemistry depending on choice of reducing agent.

Chapter 3. Anti-Anxiety Agents, Anticonvulsants, and Sedative-Hypnotics

Publisher Summary This chapter describes the novel animal test for the pharmacological characterization of anti-anxiety agents as well as a model for study of benzodiazepine (BZ) physical dependence. The course of discussion includes reviews on the mechanism of action of BZs and the chemistry, activity profiles, clinical applications, evaluation, pharmacology, metabolism, and pharmacokinetics of anxiolytics. Regarding anxiolytic agents, there have been clinical studies on the treatment of various anxiety states with bromazepam, alprazolam, chlordesmethyldiazepam, camazepam, clorazepate, halazepam, razepam, and others. Compounds found active as sedative-hypnotics include lormetazepam in a double blind study with preoperative inpatients; lorazepam in post-operative patients and in acute alcoholics; pinazepam in normal subjects; and quazepam in chronic insomniacs. As for anticonvulsants, Clonazepam was found useful in the treatment of epilepsy in a crossover comparison with valproate sodium. A study on the influence of this drug on the spontaneous EEG in rats has been published. A pilot study found clorazepate to be as effective as phenobarbital as secondary anticonvulsants incombination with phenytoin, but with fewer side effects.

D1 and D2 Dopamine Receptors: Identification by Photoaffinity Labeling and Purification by Affinity Chromatography

In an attempt to characterize the receptors which mediate the physiological actions of dopamine, we have developed several probes for the characterization of both the D1 and D2 subtypes of dopamine receptors. To identify the ligand binding site of these receptors we have developed affinity and photoaffinity probes based on the structure of high affinity selective antagonists. [125I]p(azidcphenethyl) spiperone has been used to identify the ligand binding site of the D2 dopamine receptor in several tissues (Amlaiky and Caron, 1985). More recently, our laboratory has also characterized the ligand binding subunit of the D1 dopamine by covalently incorporating a radioiodinated arylamine derivative of the selective D1 antagonist SCH-23390 into rat striatal membranes by photoaffinity crosslinking (Amlaiky et al. 1987). Another derivative of the potent D2 antagonist spiperone (carboxynethyleneoximinospiperone) has been used in the development of an affinity chromatography procedure for the purification of the D2 receptor from bovine anterior pituitary gland (Senogles et al., 1986).

Isolation And Biochemical Characterization Of The D1 And D2 Dopamine Receptors

The catecholamine, dopamine, exerts physiologic effects in both the central nervous system and the periphery. Dopamine systems in the central nervous system (CNS) have been implicated in several neurologic and psychiatric disorders such as Parkinsonism, schizophrenia, Huntington’s chorea, Tourette’s syndrome, and Lesch-Nyhan syndrome. In the periphery, dopamine plays a role in processes controlling renal vascular tone and release of the hormones, prolactin from the anterior pituitary gland and parathyroid hormone from the parathyroid gland. The symptoms of some pathological processes are ameliorated through the use of drugs targeted toward the receptors for dopamine. For example, dopamine agonists have been successfully used to treat Parkinson’s disease, hyperprolactinemia (prolactinomas), and to prevent renal ischemia associated with cardiovascular collapse (shock), and dopamine antagonists have proven useful in the treatment of schizophrenia, and Tourette’s syndrome.