We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with ...expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus B. McKernan, K. E. S. Ford, I. Bartoset al., Astrophys. J. Lett.884, L50 (2019) and is unlikely <O(0.01%)) due to intrinsic variability of this source. The lack of color evolution implies that it is not a supernova and instead is strongly suggestive of a constant temperature shock. Other false-positive events, such as microlensing ora tidal disruption event, are ruled out or constrained to be <O(0.1%). If the flare is associated withS190521g, we find plausible values of total mass M(BBH) ∼ 100 Mꙩ, kick velocity v(k) ∼ 200 km/s at θ ∼ 60° in a disk with aspect ratio H/a ∼ 0.01(i.e., disk height H at radius a) and gas density ρ ∼ 10^(−10)g/cu.cm. The merger could have occurred at a disk migration trap (a ∼ 700 r(g); r(g) ≡ GM(SMBH)/sq.c, where M(SMBH) is the mass of the active galactic nucleus supermassive black hole). The combination of parameters implies a significant spin for at least one of the black holes in S190521g. The timing of our spectroscopy prevents useful constraints on broad-line asymmetry due to an off-center flare. We predict a repeat flare in this source due to a reencountering with the disk in ∼ 1.6 yr(M(SMBH)/10^(8) Mꙩ)(a/10^(3)r(g))^(3/2).
Since the mid 1980s, there has been a great deal of enthusiasm within both academia and industry about the therapeutic potential of drugs targeting the NMDA subtype of glutamate receptors. That early ...promise is just beginning to translate into approvable drugs. Here we review the reasons for this slow progress and critically assess the future prospects for drugs that act on NMDA receptor pathways, including potential treatments for some major disorders such as stroke and Alzheimer's disease, for which effective therapies are still lacking.
MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant
GABAA receptors with comparable high affinity (0.21–0.40 nM).
However, MRK-409 has greater agonist efficacy at the α3 compared with ...α1 subtypes
(respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This
compound readily penetrates the brain in rats and occupies the benzodiazepine site of
GABAA receptors, measured using an in vivo 3Hflumazenil binding assay,
with an Occ50 of 2.2 mg/kg p.o. and a corresponding plasma EC50
of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409
produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of
anxiety with minimum effective doses corresponding to occupancies, depending on the particular
model, ranging from ∼35% to 65% yet there were minimal overt signs of
sedation at occupancies greater than 90%. In humans, however, safety and tolerability
studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a
maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a
Cmax
plasma concentration of 28 ng/mL, which, based on
the rodent plasma EC50 for occupancy of 115 ng/mL, suggested that sedation
in humans occurs at low levels of occupancy. This was confirmed in human positron emission
tomography studies, in which 11Cflumazenil uptake following a single dose of
1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of
GABAA receptor benzodiazepine binding sites by MRK-409 was below the limits of
detection (i.e. <10%). Taken together, these data show that MRK-409 causes
sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably
less than those predicted from rodent models to be required for anxiolytic efficacy
(∼35–65%). Thus, the preclinical non-sedating anxiolytic profile of
MRK-409 did not translate into humans and further development of this compound was halted.
GABAA receptors are a heterogeneous family of ligand-gated ion channels responsible for mediating inhibitory neurotransmission in the CNS. Since the identification of mammalian cDNAs encoding 13 ...GABAA-receptor subunits, the composition of native receptor molecules and their localization in the brain has been an area of intense study. We conclude that the number of major subtypes is probably less than ten but their physiological roles have yet to be clearly defined and this represents the next step in GABAA-receptor research.
γ -Aminobutyric acid type A (GABA-A) receptors are a major mediator of inhibitory neurotransmission in the mammalian central nervous system, and the site of action of a number of clinically important ...drugs. These receptors exist as a family of subtypes with distinct temporal and spatial patterns of expression and distinct properties that presumably underlie a precise role for each subtype. The newest member of this gene family is the θ subunit. The deduced polypeptide sequence is 627 amino acids long and has highest sequence identity (50.5%) with the β 1 subunit. Within the rat striatum, this subunit coassembles with α 2, β 1, and γ 1 suggesting that γ -aminobutyric acid type A receptors consisting of arrangements other than α β +γ,δ , or ε do exist. Expression of α 2β 1γ 1θ in transfected mammalian cells leads to the formation of receptors with a 4-fold decrease in the affinity for γ -aminobutyric acid compared with α 2β 1γ 1. This subunit has a unique distribution, with studies so far suggesting significant expression within monoaminergic neurons of both human and monkey brain.
GABA
A receptors are a heterogeneous family of ligand-gated ion channels responsible for mediating inhibitory neurotransmission in the CNS. Since the identification of mammalian cDNAs encoding 13 ...GABA
A-receptor subunits, the composition of native receptor molecules and their localization in the brain has been an area of intense study. We conclude that the number of major subtypes is probably less than ten but their physiological roles have yet to be clearly defined and this represents the next step in GABA
A-receptor research.
Fast inhibitory neurotransmission in the mammalian CNS is mediated primarily by the neurotransmitter γ‐aminobutyric acid (GABA), which, upon binding to its receptor, leads to opening of the intrinsic ...ion channel, allowing chloride to enter the cell. Over the past 10 years it has become clear that a family of GABA‐A receptor subtypes exists, generated through the coassembly of polypeptides selected from α1‐α6, β1‐β3, γ1‐γ3, δ, ɛ, and π to form what is most likely a pentomeric macromolecule. The gene transcripts, and indeed the polypeptides, show distinct patterns of temporal and spatial expression, such that the GABA‐A receptor subtypes have a defined localization that presumably reflects their physiological role. A picture is beginning to emerge of the properties conferred to receptor subtypes by the different subunits; these include different functional properties, differential modulation by protein kinases, and the targeting to different membrane compartments. These properties presumably underlie the different physiological roles of the various receptor subtypes. Recently we have identified a further member of the GABA‐A receptor gene family, which we have termed θ, which appears to be most closely related to the β subunits. The structure, function, and distribution of θ‐containing receptors, and receptors containing the recently reported ɛ subunit, are described.
In the accompanying paper we describe how MRK-409 unexpectedly produced sedation
in man at relatively low levels of GABAA receptor occupancy
(∼10%). Since it was not clear whether this sedation was
...mediated via the α2/α3 or α1 GABAA subtype(s), we
characterized the properties of TPA023B, a high-affinity imidazotriazine which,
like MRK-409, has partial agonist efficacy at the α2 and α3 subtype
but is an antagonist at the α1 subtype, at which MRK-409 has weak partial
agonism. TPA023B gave dose- and time-dependent occupancy of rat brain
GABAA receptors as measured using an in vivo
3Hflumazenil binding assay, with 50% occupancy
corresponding to a respective dose and plasma drug concentration of
0.09 mg/kg and 19 ng/mL, the latter of which was similar to that
observed in mice (25 ng/mL) and comparable to values obtained in baboon
and man using 11Cflumazenil PET (10 and 5.8 ng/mL,
respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey)
models of anxiety (elevated plus maze, fear-potentiated startle, conditioned
suppression of drinking, conditioned emotional response) yet had no significant
effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod,
chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to
occupancy of greater than 99%. In man, TPA023B was well tolerated at a
dose (1.5 mg) that produced occupancy of >50%,
suggesting that the sedation previously seen with MRK-409 is due to the partial
agonist efficacy of that compound at the α1 subtype, and highlighting the
importance of antagonist efficacy at this particular GABAA receptor
population for avoiding sedation in man.
PDF
