An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action.

In this overview, we discuss the discovery and development of topiramate (TPM) as an anticonvulsant, including notable aspects of its chemical, biologic, and pharmacokinetic properties. In particular, we highlight its anticonvulsant profile in traditional seizure tests and animal models of epilepsy and the results of recent electrophysiological and biochemical studies using cultured neurons that have revealed a unique combination of pharmacologic properties of TPM. Finally, we present a hypothesis for the mechanistic basis of the anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane ion channel proteins at phosphorylation sites and thereby allosterically modulates channel conductance and secondarily inhibits protein phosphorylation.

Alpha(2) adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles.

A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).

Topiramate: preclinical evaluation of structurally novel anticonvulsant.

Topiramate [TPM, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] (RWJ-17021-000, formerly McN-4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident < or = 0.5 h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)-induced clonic seizures at high doses in mice (ED50 = 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF-525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.

2-Substituted 1-azabicycloalkanes, a new class of non-opiate antinociceptive agents.

2-Substituted 1-azabicycloalkanes (3- and 5-aryloctahydroindolizines 2 and 11, 3-cyclohexyloctahydroindolizine 12, 4-aryloctahydroquinolizines 13, and 3-arylhexahydropyrrolizines 14) constitute a new class of non-opiate antinociceptive agents. These compounds demonstrated activity in the mouse abdominal constriction test and many were active in the mouse tail-flick test. trans-3-(2-Bromophenyl)octahydroindolizine (2a) did not bind to the opiate receptor nor did it affect arachidonate metabolism. 3-Aryloctahydroindolizines were prepared by catalytic hydrogenation of 1-aryl-3-(2-pyridinyl)-2-propen-1-ones. The X-ray crystal structure of (-)-2a was determined and absolute stereochemistry assigned as 3-R,8a-R.

Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships.

A series of pyrrolo[2,1-a]isoquinolines, and related compounds, were examined for antidepressant-like activity, by virtue of their antagonism of tetrabenazine-induced ptosis and sedation, and inhibition of biogenic amine uptake. Thus, we have identified some of the most potent antagonists of TBZ-induced ptosis and some of the most potent inhibitors of the uptake of dopamine, norepinephrine, and serotonin (in rat brain synaptosomes) ever reported. Compounds of particular note, in this regard, are 52b, 29b, 22b, and 48b, respectively. Biological activity was chiefly manifested by the trans isomeric class. Also, through resolution of four compounds, 7b, 24b, 37b, and 48b, biological activity was found to be associated with the (+) enantiomer subgroup (salts measured at 589 nm in MeOH), corresponding to the 6S, 10bR absolute configuration for 7b, 37b, and 48b, and the 6R,10bR configuration for 24b. An X-ray determination on (+)-24b X HBr established its absolute configuration; configurations for the other compounds were verified by enantiospecific synthesis starting with (+)-(R)-2-phenylpyrrolidine. Regarding the pendant phenyl ring, diverse substitution patterns were investigated. Those substitutions that were particularly unfavorable were 3',4',5'-trimethoxy (20b), 2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b), 3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b), 4'-methylsulfonyl (50b), and 2'-carboxy (58b). Exceedingly potent compounds, in one way or another, were 10b-12b, 22b, 23b, 25b, 28b, 29b, 33b, 45b, 48b, 51b-53b. The pattern of aromatic substitution had a strong impact on selectivity in the uptake tests (NE vs. DA vs. 5-HT). Activity was significantly diminished by methyl substitution of 7b at the 5 (65, 66), 6 (61b), or 10b (60b) position, by changing the phenyl group of 7b to cyclohexyl (67b), benzyl (68b), or H (72), by moving the phenyl group of 7b to the 5 (69) or 10b (70) position, by expansion of ring B to an azepine (78b), and by modification of ring C to an azetidine (77b), piperidine (75b), or azepine (74b). The interaction of selected analogues with various CNS receptors is reported. Little affinity was shown for the muscarinic cholinergic receptor, suggesting a lack of anticholinergic side effects. Interestingly, 24b and 33b displayed a high affinity for the serotonin-2 receptor, analogous to mianserin and clomipramine. After the body of data was reviewed, derivatives 24b and 48b were chosen for advanced development.

Preclinical evaluation of McN-5707 as a potential antidepressant.

Based on its activity in a variety of tests in vivo and in vitro McN-5707 [trans-6-(2-chlorophenyl)-1,2,3,5,6,10b-hexahydropyrrolo- (2,1-a)isoquinoline] is a novel potential antidepressant. McN-5707 blocked tetrabenazine-induced sedation and ptosis in mice and rats, and potently inhibited the uptake of norepinephrine by synaptosomes from rat hypothalamus (Ki approximately 2 nM), and the uptake of serotonin by synaptosomes from rat cerebral cortex (Ki approximately 10 nM). McN-5707 also inhibited the uptake of dopamine by synaptosomes from rat striatum (Ki approximately 40 nM); however, the stereotypic behavior often caused by dopamine uptake inhibitors was not evident in rats at doses of 300 mg/kg (p.o.) or less. In receptor binding assays, McN-5707 potently inhibited ketanserin binding to serotonin 5-HT2 receptors in synaptic membranes from rat cerebral cortex (apparent Ki approximately 8 nM). In mice, McN-5707 antagonized 5-hydroxytryptophan-induced head twitches. Spiperone binding to dopamine D2 receptors in synaptic membranes from rat striatum was weakly inhibited by McN-5707 (apparent Ki approximately 400 nM), as was the binding of WB4101 to alpha-1 adrenergic receptors (apparent Ki approximately 150 nM). McN-5707 was essentially inactive as an inhibitor of [3H]clonidine binding to alpha-2 adrenergic receptors and of [3H]quinuclidinyl benzilate binding to muscarinic receptors. In experiments with guinea pig ileum, McN-5707 weakly antagonized histamine-induced contractions and exhibited virtually no cholinergic or anticholinergic activity. Our observations indicate McN-5707 possesses attributes of both tricyclic and newer atypical antidepressants because it inhibits the uptake of both norepinephrine and serotonin, and blocks 5-HT2 receptors, but lacks some of the anticholinergic and behavioral properties often associated with them.

Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate and related compounds.

Novel sugar sulfamate 1 (McN-4853, topiramate) has been found to exhibit potent anticonvulsant activity analogous to that of phenytoin. In the maximal electroshock seizure test, orally at 2 h in mice, 1 had an ED50 of 39 mg/kg. Orally, 1 had a duration of action in excess of 8 h. Other aspects of the pharmacology of 1, as well as neurochemistry and carbonic anhydrase inhibition, are discussed. The conformational behavior of 1 in solution and in the solid state is discussed. A series of analogues of 1 were synthesized and examined for anticonvulsant properties.

Structure-activity studies on antidepressant 2,2-diarylethylamines.

A series of 2,2-diarylethylamine derivatives has been examined for potential antidepressant activity in the tetrabenazine (TBZ) test. Diethanolamine 4 (McN-4187) was one of the more potent compounds despite its polar alcohol functionalities [ED50 values of 15 mg/kg (exploratory activity) and 1.5 mg/kg (ptosis)]. Structure-activity relationships are described. Minor structural modifications of 4 were sufficient to strongly attenuate activity. For example, changing one phenyl group to a 2-thienyl, cyclohexyl, or 3,4-dimethoxyphenyl group greatly reduced activity. Replacing both phenyl groups by 4-chlorophenyl groups also dissipated activity. The bisethanol functionality was not essential for activity (q.v. 17-19 in Table I). Although 17-19 compared well with 4 in the TBZ assay, only 19 (like 4) showed a satisfactory profile in the maximal electroshock seizure threshold test.

Anti-inflammatory and antiarthritic evaluation of acetaminophen and its potentiation of tolmetin.

The data obtained from 5-day and long-term evaluations of acetaminophen (APAP) using the adjuvant arthritis rat model, demonstrated the anti-inflammatory and antiarthritic activities of APAP. The analgesic, anti-inflammatory and antiarthritic activities of tolmetin were significantly potentiated when used in combination with APAP. Inasmuch as APAP, up to 2.0 mg/kg/day, does not produce ulcerogenic effects and does not potentiate the ulcerogenic potency of tolmetin, the therapeutic safety of the APAP-tolmetin combination is much superior to tolmetin alone as determined by these preclinical evaluations. Further studies will be necessary to identify the existence of other side effects, which may or may not be potentiated, before any clinical studies can be contemplated.

Synthesis and stereochemistry of 7-phenyl-2-propionanilidobenzo[a]quinolizidine derivatives. Structural probes of fentanyl analgesics.

The for diastereomers of N-(1,3,4,6,7,11b-hexahydro-7-phenyl-2H-benzo[a]quinolizin-2-yl)-N-phenylpropanamide (7c, 7d, 9c, and 9d), which are conformationally restricted analogues of fentanyl, were synthesized and separately tested for analgesic activity and affinity for the opiate receptor of rat brain. Stereochemical assignments for 7c, 7d, 9c, and 9d were deduced from NMR spectral analyses. Conformational analysis revealed that the 2 alpha isomers (7d and 9d) exist in solution as mixtures of cis- and trans-fused conformers with ca. 90 and 45% cis form, respectively. Other compounds (12a, 12b, and 14) related to these propionanilides were also prepared, stereochemically characterized, and tested. Weak analgesic activity was observed for 7d, and both 7d and 9d bound to the opiate receptor with an I50 of ca. 1100 and 1500 nM, respectively (ca. 0.5% of fentanyl and 2% of morphine). The analgesic activity of 7d was abolished by the opiate antagonist naloxone.

Evaluation of the analgesic properties of zomepirac.

Zomepirac, an inhibitor of prostaglandin biosynthesis, was evaluated for analgesic activity in a number of pharmacological screens. In the acetylcholine writhing test, zomepirac was found to be more potent than codeine, pentazocine, aspirin, and acetaminophen and equivalent in potency to morphine. Zomepirac was inactive in a number of tests that detect narcotic agents, suggesting that the drug will not induce physical dependence. The possibility of a central nonnarcotic as well as a peripheral analgesic mechanism merits consideration.

2-Pyrrolidinylideneureas, a new class of central nervous system agents.

A series of N-aryl-N'-(1-methyl-2-pyrrolidinylidene)ureas was prepared and screened for pharmacological activity. Congeners possessing either phenyl or phenyl substituted with 4-nitro, 3-bromo, 3-chloro, 3-fluoro, and 3-methyl groups were found to demonstrate anxiolytic activity. 2,6-Disubstitution of the phenyl ring with methyl, chloro, and bromo imparted potent muscle-relaxant properties which appear to be centrally mediated. A significant separation of the anxiolytic and muscle-relaxant properties from other CNS activities, e.g., anticonvulsant, sedative, and hypnotic, was achieved.

Pharmacological profile of N-(2,6-DIMETHYLPHENYL)-N-(1-methyl-2pyrrolidinylidene)urea, xilobam, a new centrally acting skeletal muscle relaxant.

The pharmacological profile of a new centrally acting skeletal muscle relaxant, xilobam, is described and compared to that of existing skeletal muscle relaxants. The potencyof xilobam, administered intravenously, is approximately ten times that of methocarbamol in the linguomandibular assay in the cat. When evaluated in the strychnin assay in the mouse, the potency of xilobam is approximately seven times that of chlorzoxazone and eleven tomes that of methocarbamol and five times that of metaxalone. In contrast to methocarbamol, xilobam exhibits little or no sedative activity and appears devoid of antianxiety properties. When administered to non-anesthetized dogs, xilobam and other centrally acting muscle relaxants, such as chlorzoxazone and methocarbamol, increased arterial pressure and heart rate. Mydraiasis, vocalization and muscle rigidity were concomitantly observed. These effects appear to be centrally induced. It is concluded that xilobam appears to be a potent centrally acting muscle relaxant which should not be sedating or anxiolytic in man.