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Interaction of Benzodiazepines with Central Nervous Glycine Receptors: Possible Mechanism of Action (Strychnine Binding/Behavioral Tests) ANNE B

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Interaction of Benzodiazepines with Central Nervous Glycine Receptors: Possible Mechanism of Action (Strychnine Binding/Behavioral Tests) ANNE B Proc. Nat. Acad. Sci. USA Vol. 71, No. 6, pp. 2246-2250, June 1974 Interaction of Benzodiazepines with Central Nervous Glycine Receptors: Possible Mechanism of Action (strychnine binding/behavioral tests) ANNE B. YOUNG, STEPHEN R. ZUKIN, AND SOLOMON H. SNYDER* Departments of Pharmacology and Experimental Therapeutics and Psychiatry and the Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Communicaed by Cheves Walling, January 29, 1974 ABSTRACT Interaction of 21 benzodiazepines with the ously (4). The specific activity of the labeled strychnine was glycine receptor in the brainstem and spinal cord of rat have been evaluated in terms of their displacement of 13 Ci/mmol, with concentrations determined by comparison ['HIstrychnine binding. The rank order of potency of the with the ultraviolet absorption of standard solutions at 254 21 drugs in displacing specific ['H1strychnine binding cor- nm. relates (p < 0.005) with their rank order of potency in a variety of pharmacological and behavioral tests in Tissue Preparation. Male Sprague-Dawley rats (100-150 g) humans and animals that predict clinical efficacy. There were decapitated and the brainstems and spinal cords re- is a 50-fold variation in potency of the series of benzo- moved. Crude synaptic membrane fractions of these tissues diazepines with mean effective dose (ED5.) values ranging were prepared by the differential centrifugation technique from 19juM to >1000 pM. Diazepam (Valium®) and chlor- diazepoxide (Librium®) have EDN's of 26 MM and 200 pM, previously reported (4). respectively, whereas the ED5. for glycine is 25 ;M. The in- hibitory effects of 10 of the agents in two other central ner- Binding A8say. To measure specific binding of strychnine vous system membrane receptor assays, for the opiate to spinal cord membranes, aliquots of crude synaptic mem- receptor and the muscarinic cholinergic receptor, do not branes (0.3-1.0 mg of protein) were incubated in triplicate at correlate with any of the in vivo pharmacologic and be- 40 for 10 min in 2 ml of 0.05 M Na-K phosphate buffer (pH havioral tests. The benzodiazepines may exert their anti- 7.1) containing 200 mM NaCl and 2 nM anxiety, anticonvulsant and muscle-relaxant effects by ['H]strychnine mimicking the effects of the neurotransmitter glycine at (38,000 cpm) alone or in the presence of 1 mM glycine or its central nervous system receptor sites. various concentrations of drugs. After incubation, the reaction was terminated by centrifugation for 10 min at 48,000 X g. The most prominent clinical actions of the benzodiazepines, a The supernatant fluid was decanted, and the pellet rinsed with class of drugs including such widely used agents as diazepam 5 ml, then 10 ml of ice-cold 0.15 M NaCl. Bound radioactivity (Valium®) and chlordiazepoxide (Librium®), are relief of was extracted into 1 ml of Protosol (New England Nuclear anxiety, muscular relaxation, and amelioration of convulsive Corp.), 10 ml of toluene phosphor were added and radio- states. A variety of evidence suggests that these drugs en- activity assayed by liquid scintillation spectrometry (Packard hance polysynaptic inhibitory processes in the spinal cord, Tricarb model 3385 or 3375), at a counting efficiency of 34%. brain stem, and thalamus (1). Many inhibitory processes in Specific ['Histrychnine binding was obtained by subtract- these areas are medicated by glycine-containing interneurons ing from the total bound radioactivity the amount not dis- (2, 3). Recently we have identified specific binding of radio- placed by high concentrations (1 mM) of glycine. labeled strychnine associated with glycine receptor sites in the mammalian spinal cord, brain stem and thalamus (4). The Drug. Benzodiazepines were very kindly donated by Dr. relative abilities of amino acids to mimic the neurophysiologic W. Scott and Dr. R. Kuntzman of Hoffman-La Roche, New actions of glycine correlate with their affinities for these bind- Jersey. The structures of these drugs and their Roche ("RO5") ing sites, and the regional distribution of specific strychnine designations are shown in Figs. 1 and 2. binding in the central nervous system closely parallels the dis- Carisoprodol, meprobamate, methaqualone, and tybamate tribution of glycine as well as neurophysiological sensitivity to were kindly donated by Carter-Wallace Laboratories of New glycine (3, 5). In the present study we have examined the Jersey; methocarbamol by Robins Research Laboratories; relative affinities of a series of benzodiazepines for specific and chlorzoxazone from McNeil Laboratories, Fort Washing- strychnine-binding sites in the brain stem, spinal cord, and ton, Pa. Mephenesin was kindly donated by Dorsey Labora- thalamus of the rat and have correlated this data with the tories, Lincoln, Neb. pharmacological actions of the benzodiazepines. Specific binding of ['H]dihydromorphine was assayed in brain homogenates as described separately (9). MATERIALS AND METHODS Binding of ['H ]quinuclidinyl benzilate (QNB) to muscarinic Strychnine was labeled by catalytic tritium exchange at cholinergic receptors was assayed as previously described New England Nuclear Corp. and purified as described prey- (10). RESULTS AND DISCUSSION Abbreviation: ED5o, mean effective dose. * To whom reprint requests should be sent at the Department of A variety of benzodiazepines (Figs. 1 and 2) are effective in Pharmacology. displacing specific [3H]strychnine binding (Table 1). The 2246 Downloaded by guest on September 25, 2021 Proc. Nat. Acad. Sci. USA 71 (1974) Benzodiazepines and Glycine Receptors 2247 RO 5-6789 (OXAZEPAM) H° 4 N cK%> p RO 5-3785 RO 5-2181 H ,0 NHCH DRUG RI Rp x H RO 5-2904 - CFN - -H OH CI NH RO 5-3059 _ _-Hu (NITRAZEPAM) RO 5-3027 -Cl e- CI -H RO 5-4023 - NO2 O-C I -H (CLONAZ EPAM) c-CF3 -H RO 5-3590 -NO2 RO 5-4933 H RO 5-3636 CHI RO 5-3350 -Br -H (BROMAZEPAM) O-P HCI RO 5-4528 -CN -CH3 cl\CHI DIAZE PAM -Cl -CH3 RO 5-4200 o-CF -CH3 (FLUNITRAZEPAM) -NOg RO 5-4864 -Cl p..CI -CH3 RO 5-4556 CH3 RO 5-4964 Cr3 RO 5-5807 -Cl -CHgCONHCH3 (MEDAZEPAM) RO 5-6901 -Cl O-F -CH (FLURAZEPAM) H2N(CgH5)g *HCI *2 HCI o-F RO 5-6227 -Cl -(CH9)3N (C"2)3 CIl~ HZNXN FIG. 1. Structures of a series of 1,3-dihydro-5-phenyl-2H-1,4- benzodiazepine-2-one derivatives. FIG. 2. Structures of benzodiazepine derivatives in which ring series of 21 drugs exhibits a 50-fold variation in potency with B differs from that of the drugs depicted in Fig. 1. EDso values ranging from 19MuM to >1000 MM. By comparison, glycine has an ED50 of 25 ,M. Diazepam (Valium®) and elicited by minimal or maximal electroshock; these tests are chlordiazepoxide (Librium®), the two most frequently pre- also less effective predictors of benzodiazepine action in scribed drugs in the United States, have ED50 values of 26 humans (6). MAM and 200 MM, respectively. Nitrazepam (Mogadon®) and Thirteen of the benzodiazepines (Fig. 1) possess a common oxazepam (Serax®), also used in this country as anti-anxiety B-ring structure, except for variations in the X-substituent. agents, have ED50 values of 20 ,M and 90 MuM, while fluraze- Dreiding molecular models of glycine can be readily super- pam (Dalmane®), used as a hypnotic, has an ED5o of 28 MM. imposed upon a portion of the B-ring of these 13 agents. By The most potent drug in our series was flunitrazepam, which contrast, models of glycine cannot be as effectively super- is used clinically in Europe. Clonazepam has an ED60 of 32.5 imposed upon the B-rings of the drugs shown in Fig. 2. Inter- MAM and medazepam, used in Europe, is much less effective, estingly, the drugs having the B-ring structure shown in Fig. 1 with an ED5o of 340MAM. tend to be more potent than those having the variant struc- To ascertain whether the interactions of benzodiazepines tures shown in Fig. 2, as indicated in Fig. 3, where the latter with specific strychnine-binding sites are related to their are italicized. The mean ED50 for the drugs in Fig. 1 is signifi- clinical activities, we compared the clinical potency and ac- cantly lower than that for the drugs in Fig. 2 by a Mann- tivity in pharmacological tests that predict clinical activity Whitney U-test (p < 0.01). Despite this implication that (6) with potency in displacing [3H]strychnine binding (Fig. 3, potency correlates with structural similarity to glycine, recent Table 2). Potencies in displacing [8H]strychnine binding cor- studies indicate that strychnine and glycine interact at recep- relate very closely with potencies in a "human bioassay" tor sites in an allosteric fashion (7). Thus, some agents such as based on the minimal dose at which 50% of subjects experi- diazonium tetrazole and acetic anhydride strongly inhibit the ence subjective effects. Similar close correlations occur ability of glycine to displace [3H]strychnine binding but only between displacement of [3H strychnine binding and the slightly affect the ability of nonradioactive strychnine to dis- potencies of benzodiazepines in several animal tests which place [3H]strychnine. Moreover, the Hill coefficient, n, for have been found to be effective predictors of drug potency in displacement of bound [3Hjstrychnine by nonradioactive humans; thus, the potencies in the mouse antifighting, mon- strychnine is 1.0, while the coefficient for glycine displacement key taming, mouse and cat muscle relaxation, antipentylene- of ['H]strychnine is 1.7, indicating a cooperative interaction tetrazole seizure and rat continuous avoidance tests correlate of glycine with strychnine binding (Fig. 4). Displacement of with the strychnine displacement potencies in highly signifi- [1H]strychnine by benzodiazepines has a Hill coefficient of cant fashion. Considerably lower correlation is obtained with 1.0, the same as for strychnine (Fig.
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