CNS drug reviews最新文献

The synthetic compound HU 210 displays a multiplicity of biochemical, pharmacological, and behavioral effects, most of which have been demonstrated to be dependent on a selective agonistic activity at CB₁ and CB₂ cannabinoid receptors and to involve the main neurotransmitter systems. Results obtained in various studies suggest a potential clinical application of this highly potent drug (e.g., as antipyretic, antiinflammatory, analgesic, antiemetic, and antipsychotic agent) as well as its usefulness in research aimed to develop a better understanding of the involvement of the endogenous cannabinoid system in a number of physiopathological functions.

Thromboembolic stroke is a severe, disabling disease characterized by an abrupt reduction of cerebral blood flow, which leads to deprivation of oxygen and nutrients to neuronal tissue, followed by permanent brain damage. Evidence has been accumulated to implicate excitotoxicity in the pathogenesis of ischemic brain injury. Overstimulation of excitatory amino acid receptors becomes deleterious for neuronal cell survival. Glutamate antagonists can ameliorate the ischemic injury by any of several mechanisms. Because blockade of the glycine site of the N-methyl-D-aspartate (NMDA) receptor seems to offer a better side-effect profile, glycine antagonists are attractive targets for blocking excitotoxicity following stroke.

GV150526 is a selective and potent glycine antagonist at the NMDA receptor complex. It binds to the glycine site with both high affinity and high selectivity in in vitro binding studies. In vivo studies have shown that GV150526 significantly reduces infarct volume in the middle cerebral artery occlusion model of stroke. This effect remained statistically significant, even if treatment was delayed for as long as 6 h post-occlusion. GV150526 showed no evidence of adverse effects usually associated with NMDA receptor blockers, such as neuronal vacuolization in standard assays or cognitive impairment in behavioral tests. GV150526 had no significant treatment-related respiratory or cardiovascular effects or effects on behavior, body temperature, or blood pressure in mice or rats. Pharmacokinetic studies indicated that GV150526 has low clearance and volume of distribution in both the rat and the dog. Preclinical toxicology studies have shown that the compound is well tolerated in both species. Phase I/II studies were undertaken to assess the safety, tolerability, and pharmacokinetics of GV150526 in healthy volunteers and acute stroke patients, and from these a dose was selected to be studied in Phase III clinical trials. These efficacy studies have now completed recruitment and data reconciliation is ongoing. GV150526 has the potential to be an effective therapy for acute ischemic stroke.

5-HT_1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5-HT_1B receptor inverse agonist, SB-236057-A (1′-ethyl-5-(2′-methyl-4′-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro (furo[2,3-f]indole-3,4′-piperidine) hydrochloride). SB 236057-A has been shown to have high affinity for human 5-HT_1B receptors (pK_i= 8.2) and displays 80 or more fold selectivity for the human 5-HT_1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT_1B receptors SB-236057-A displayed inverse agonism (pA₂= 8.9) using [³⁵S]GTPγS binding, and silent antagonism (pA₂= 9.2) using cAMP accumulation. SB-236057-A also acted as an antagonist at the 5-HT terminal autoreceptor as measured by [³H]5-HT release from electrically stimulated guinea pig and human cortical slices.

In the guinea pig, pharmacokinetic analysis demonstrated that SB-236057-A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints.

In vivo microdialysis studies demonstrated that SB-236057-A is an antagonist in the guinea pig cortex but has no effect on extracellular 5-HT levels per se. In contrast, SB-236057-A increased extracellular 5-HT levels in the guinea pig dentate gyrus. This increase in 5-HT release was comparable to that observed after 14 days of paroxetine administration.

SB-236057-A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5-HT autoreceptor is of the 5-HT_1B subtype. It appears that acute 5-HT_1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.

Phenibut (β-phenyl-γ-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA-mimetic, primarily at GABA_B and, to some extent, at GABA_A receptors. It also stimulates dopamine receptors and antagonizes β-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut. This article reviews the structure-activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre- or post-operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post-traumatic stress, stuttering and vestibular disorders.