Selective binding of YM-09151-2, a new potent neuroleptic, to D2-dopaminergic receptors.

Abstract

Abstract-Effectsof YM-09151-2 and five other neuroleptics (haloperidol, spiperone, chlorpromazine, sulpiride and clozapine) on the binding of [3H]-ligands to nine different receptors (a,-adrenergic, a2-adrenergic, Q-adrenergic, muscarinic, D2-dopaminergic, H1-histaminergic, 5HT,-serotonergic, 5HT2-serotonergic and opiate receptors) and on dopamine-sensitive adenylate cyclase were determined using brain membranes in the rat, guinea-pig and dog. The affinity of YM-091 51-2 for D2-receptors with a K, value of 0.1 nM was more than 1000-times higher than that for the other receptors and dopamine sensitive adenylate cyclase, and it was the greatest among the nueroleptics tested.A close relationship between antidopami nergic and antischizophrenic effects of neu roleptics has been demonstrated by phar macological, electrophysiological, histo chemical and biochemical studies (1). Recent studies have also shown multiplicity of the dopaminergic receptors, referred to as D, (adenylate cyclase-linked), D2 (non adenylate cyclase-linked), D3 (non-adenylate cyclase-linked) and D4 (inversely adenylate cyclase-linked) according to the terminology proposed by Seeman (1, 2), in the brain; and the antischizophrenic effect seems to be at least partly attributable to a blockade of a particular type (D2) of the dopaminergic receptors. However, usefulness of the drugs in the treatment of schizophrenic patients is often limited, partly due to insufficient specificity in the affinity for the D2 dopaminergic receptors, which occasionally results in undesirable side effects such as orthostatic hypotension and thirst. Lack of specificity of neuroleptics for the D2-receptor also makes it difficult to attribute their dopaminergic functions to the D2-receptor.

Parallelism between Avoidance-Suppressing and Prolactin-Increasing Effects of Antipsychotic Drugs in Rats

“…These possibilities indicate that the slow onset of the avoidance-suppressing effect of SP observed in the present study is probably not due to the experimental procedure used, but rather due to the ability of the drug to hardly cross the blood-brain barrier. Actually, YM (a similar D2 blocking agent that is a benzamide derivative), (22) which can readily pass through the barrier and exhibits potent avoidance-suppressing effect (12, 13), showed almost parallel avoidance suppression to the increase in serum prolactin level in the present study.…”

“…It is well known that SP, a D2 blocking agent (22), elicits little effect on avoidance responses (11-13). Kuribara and Tadokoro (11) investigated the avoidance-suppressing effects of 28 kinds of antipsychotic drugs on both continuous and discriminated avoidance responses in rats over a 120 min period.…”

Substrate specificity of benzamide synthetase involved in 4-hydroxy-3-nitrosobenzamide biosynthesis

“…11 The current study further examined the amino-acceptor substrate specificity of NspN. Several benzamide derivatives are used as therapeutic agents for psychiatric diseases (for example, sulpiride, amisulpride, sultopride 12 and nemonapride 13 ), as analgesic (for example, salicylamide 14 ) and as gastrointestinal agents (for example, metoclopramide 15 and itopride 16 ). Knowledge of the amino-acceptor substrate specificity of NspN would significantly aid the development of combinatorial biosyntheses using benzamide synthetases.…”

Simultaneous Demonstration of Neurotransmitter and Receptor Systems of the Rat Brain Using In Vivo Double Autoradiography.

“…In the present study, we employed double-labeled autoradiography in an attempt to simultaneously observe the physiological conditions in vivo of both the neurotransmitter, dopamine, at the presynaptic sites (Wooten and Home 1982) and the binding activities of the specific receptor, dopamine D2i at the postsynaptic sites of the striatum of the rat brain which were distributed in the dopaminergic nerve terminals of the nigrostriatal tract. A tritiated form of YM-09151-2, cis-N-(1-benzyl-2-methyl-3-pyrrolidinyl)-5-chloro-2-methoxy-4-methylaminobenzamide, a potent dopamine D2 receptor antagonist, has been used to label D2 receptors in dog (Niznik et al 1985) and rat (Terai et al 1983) striatal membrane homogenates with high affinity and low levels of …”