Synthesis and biological activity of 3-[2-(dimethylamino)ethyl]-5-[(1,1-dioxo-5-methyl-1,2,5-thiadiazolidin- 2-yl)-methyl]-1H-indole and analogues: agonists for the 5-HT1D receptor.

A novel series of 5-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)tryptamines was designed, synthesized, and evaluated as 5-HT1D receptor agonists. Compounds such as 8d,f,k were identified which had comparable affinity, potency, and receptor selectivity to that of the antimigraine drug sumatriptan. Both 8d,k were found to be well absorbed in the rat with oral bioavailabilities of 66% and 62%, respectively. Additionally, 8d was found to be selective over other non-serotonergic receptors and exhibited relatively low central nervous system penetration.

L-689,660, a novel cholinomimetic with functional selectivity for M1 and M3 muscarinic receptors.

1. L-689,660, 1-azabicyclo[2.2.2]octane, 3-(6-chloropyrazinyl)maleate, a novel cholinomimetic, demonstrated high affinity binding (pKD (apparent) 7.42) at rat cerebral cortex muscarinic receptors. L-689,660 had a low ratio (34) of pKD (apparent) values for the displacement of binding of the antagonist ([3H]-N-methylscopolamine ([3H]-NMS) compared with the displacement of the agonist [3H]-oxotremorine-M ([3H]-Oxo-M), in rat cerebral cortex. Low NMS/Oxo-M ratios have been shown previously to be a characteristic of compounds that are low efficacy partial agonists with respect to stimulation of phosphatidyl inositol turnover in the cerebral cortex. 2. L-689,660 showed no muscarinic receptor subtype selectivity in radioligand binding assays but showed functional selectivity in pharmacological assays. At M1 muscarinic receptors in the rat superior cervical ganglion, L-689,660 was a potent (pEC50 7.3 +/- 0.2) full agonist in comparison with (+/-)-muscarine. At M3 receptors in the guinea-pig ileum myenteric plexus-longitudinal muscle or in trachea, L-689,660 was again a potent agonist (pEC50 7.5 +/- 0.2 and 7.7 +/- 0.3 respectively) but had a lower maximum response than carbachol. In contrast L-689,660 was an antagonist at M2 receptors in guinea-pig atria (pA2 7.2 (95% confidence limits 7, 7.4)) and at muscarinic autoreceptors in rat hippocampal slices. 3. The putative M1-selective muscarinic agonist, AF102B (cis-2-methylspiro-(1,3-oxathiolane 5,3')-quinuclidine hydrochloride) was found to have a profile similar to L-689,660 but had up to 100 times less affinity in binding and functional assays.RS-86 (2-ethyl-8-methyl-2,8-diazospiro[4,5]decan 1,3-dionehydrochloride) also had lower affinity than L-689,660, and had no binding selectivity for muscarinic receptor subtypes. RS-86 had a higher NMS/Oxo-M ratio than L-689,660 and was a full agonist at MI,M2 and M3 receptors in the functional pharmacological assays.4. The functional selectivity of L-689,660 in muscarinic pharmacological assays is consistent with the effects of a low efficacy partial agonist in tissues with different effective receptor reserves.

A second generation of non-peptide cholecystokinin receptor antagonists and their possible therapeutic potential.

The profile of an acidic series of benzodiazepine CCK-B receptor antagonists is described. The tetrazolyl urea derivative L-368,935 had high affinity (CCK-B IC50 0.1 nM) and was one of the most selective (CCK-B/CCK-A 10,000) CCK-B antagonists known. L-368,935 was a CCK-B antagonist with high affinity on the rat ventromedial hypothalamic slice preparation (Kb 0.6 nM) and also blocked pentagastrin-induced calcium mobilization in GH3 cells. L-368,935 had potent in vivo activity and antagonized pentagastrin-induced gastric acid secretion in the anesthetized rat and CCK-8S-induced aspartate release using microdialysis in the striatum of conscious rats. Activity within the central nervous system was confirmed by a mouse ex vivo binding assay and by direct measurement of the compound within the central nervous system using an HPLC assay. A second generation of CCK-B receptor antagonists such as L-368,935 will be important in determining the therapeutic potential of this class of compound in man.

L-687,306: a functionally selective and potent muscarinic M1 receptor agonist.

The oxadiazole L-687,306 is a high affinity muscarinic agonist with a N-methylscopolamine/oxotremorine-M binding profile predictive of a partial agonist. L-687,306 showed marked selectivity in functional pharmacological assays. L-687,306 was a partial agonist at muscarinic M1 receptors in the rat ganglion but a high affinity competitive antagonist at guinea-pig cardiac M2 and ileal M3 muscarinic receptors. This compound gives an opportunity to study receptor reserve involved in muscarinic receptors in vitro and in vivo.

The relationship between articulation time and memory performance in verbal and visuospatial tasks.

The number of verbal items which can be recalled immediately is related to the rate at which an individual can speak. Subvocal rehearsal, or articulatory recoding in working memory, has been assumed to mediate this relation. For spatial items recalled in order there is also a relationship with articulation rate, which is not related to verbal rehearsal of the items. One reason for this might be that the relationship is mediated by speed of memory scanning for serial position tags in a memory set, which is related to processing speed. Subjects were asked to perform visuospatial memory tasks which involved serial position and visuospatial memory tasks in which serial position was not involved. They also performed a digit span task. The results indicated that the visuospatial memory tasks were highly related, that they were only weakly related to digit span, and that articulation rate was correlated with every measure of memory performance used, whether serial position was involved or not. There is no support for the hypothesis that speed of scanning for serial position information in immediate spatial memory leads to a relationship with articulation rate, nor is there any support for the view that memory span tasks in different domains share resources for dealing with serial order. The results are discussed in relation to Cowan, Keller, Hulme, Roodenrys, McDougall & Rack's (1994) suggestion that the relationship between articulation rate and memory span may be mediated by general processing speed.

Interference in immediate spatial memory.

It has been suggested that maintenance in visuospatial immediate memory involves implicit motor processes that are analogous to the articulatory loop in verbal memory. An alternative account, which is explored here, is that maintenance is based on shifts of spatial attention. In four experiments, subjects recalled spatial memory span items after an interval, and in a fifth experiment, digit span was recalled after an interval. The tasks carried out during the interval included touching visual targets, repeating heard words, listening to tones from spatially separated locations, pointing to these tones, pointing to visual targets, and categorizing spatial targets as being from the left or right. Spatial span recall was impaired if subjects saw visual targets or heard tones, and this impairment was increased if either a motor response or a categorical response was made. Repeating words heard in different spatial locations did not impair recall, but reading visually presented words did interfere. For digit span only, the tasks involving a verbal response impaired recall. The results are interpreted within a framework in which active spatial attention is involved in maintaining spatial items in order in memory, and is interfered with by any task (visual, auditory, perceptual, motor) that also makes demands on spatial attention.

Characteristics of spatial memory span: is there an analogy to the word length effect, based on movement time?

In studies of verbal short-term memory it has been shown that the length of words to be remembered affects the size of memory span. This word-length effect is attributed to relationships between the rate of rehearsal of verbal material and the time it takes to speak the words being rehearsed. For spatial memory span there may also be an internal rehearsal system linked to overt responding, and if there is a strong analogy to be drawn between the verbal and spatial domains then movement time between spatial targets should predict the number of spatial locations that can be recalled. In the experiments reported here the time taken to move between spatial targets is varied by altering the size of targets and the distance between them. No difference between span performance on a nine-block spatial span task were found, either on immediate recall or on recall after an interval. When recall is of items from an array of 27, grouped in nine sets of three, with only one location in any set being presented on any trial, there is an effect of display size. This effect is consonant with the argument that movement time is related to spatial rehearsal, but other explanations are also possible. However, if recall in this task is scored over the nine sets rather than over the 27 items, then there is no difference between the displays. The results indicate that performance on the normal nine-block spatial-span task cannot be predicted by movement time.

Serial order in spatial immediate memory.

Serial order effects in spatial memory are investigated in three experiments. In the first an analysis of errors in recall data suggested that immediate transpositions were the most common error and that order errors over 2 or 3 adjacent items accounted for the majority of errors in recall. The first and last serial positions are less error-prone than is the middle position in sets of six and seven items. A second experiment investigated recognition of transpositions and found that immediate transpositions were hardest to recognize but that a traditional serial position effect was not found. This may be due to the difficulty of maintaining one set of spatial items when another set is presented for comparison. A probe experiment, in which subjects were asked to recognize whether a single item came from a memory set and then to assign it to its position in the set indicated that the first and last positions were remembered more accurately than were central positions. The combination of serial order data in recall and position data suggests that there are similarities between serial order and position effects in the verbal and spatial domains and that serial order in spatial sequences is position-based.

Long-term retention deficits in two cases of disproportionate retrograde amnesia.

Abstract The status of very long-term retention, together with detailed brain imaging correlates, is presented in two patients with disproportionately dense retrograde amnesia. The first patient suffered a severe closed head injury and was left with dense autobiographical amnesia for events that she had experienced prior to her injury. She showed relatively mild, patchy memory impairment on standard anterograde memory tests. Postinjury autobiographical memory was relatively spared. However, postinjury long-term knowledge acquisition was significantly impaired. The second patient also suffered a severe head injury and was left with marked retrograde amnesia for events that she had experienced prior to her injury. She also showed relatively mild, patchy impairment on standard anterograde memory tests. Using specially designed tests, this patient showed normal immediate learning and delayed recall using a range of materials, but displayed significantly faster rate of forgetting over a period of 6 weeks than control subjects who were matched on initial delayed levels of retention. In both cases, there was major pathology in the region of the left temporal lobe, with lateral structures being more affected than medial structures. Our findings provide further evidence relating to the independence of certain anterograde and retrograde memory mechanisms, and support recent observations (De Renzi & Lucchelli, 1993) that link some instances of retrograde amnesia to impairment in very long-term retention. The possibility is raised that some forms of retrograde amnesia, such as the present cases, represent a type of "disconnection syndrome," whereby visual-semantic and other associations are disconnected from verbal representations of such associations. Lesions to intrahemispheric fasciculi or similar association fibers, in combination with lesions to critical anterior or posterior cerebral structures, may play an important role in such a disconnection.

Herpes simplex encephalitis: long term magnetic resonance imaging and neuropsychological profile.

The first comprehensive in vivo documentation of the long term profile of pathological and spared tissue is described in a group of 10 patients with a diagnosis of herpes simplex encephalitis, who were left with memory difficulties as a major residual sequel of their condition. With a dedicated MRI protocol, which included high resolution images of temporal lobe and limbic system areas, data are provided on structures that have recently gained importance as anatomical substrates for amnesia. The major features of the lesion profile were: (1) unilateral or bilateral hippocampal damage never occurred in isolation, and was often accompanied by damage to the parahippocampus, the amygdala, specific temporal lobe gyri, and the temporal poles; (2) the insula was always abnormal; (3) neocortical temporal lobe damage was usually unilateral or asymmetric. It never occurred in isolation, and was invariably associated with more medial pathological changes; (4) anterior and inferior temporal lobe gyri were damaged more often and more severely than posterior and superior temporal lobe gyri; (5) pronounced abnormality was often present in the substantia innominata (region of the basal forebrain/anterior perforated substance); (6) there was evidence of significant abnormality in the fornix; (7) there was evidence of damage to the mammillary bodies; (8) thalamic nuclei were affected in around 50% of cases, with damage usually unilateral; (9) frontal lobe damage was present in a few patients, and affected medial areas more than dorsolateral areas; (10) there was some involvement of the striatum, although this was usually unilateral and mild; (11) there was usually limited involvement of the cingulate gyrus and of the parietal and occipital lobes; (12) the cerebellum and brain stem were never damaged. Lesion covariance analysis indicated a close relation between the presence of abnormalities in temporal lobe and limbic-diencephalic regions. Unlike severe head injury, lesions in the temporal pole were not associated with the presence of lesions in the orbitofrontal cortex. Long term neuropsychological impairments were characterised by a dense amnesia in 60% of cases, and a less serve but noticeable anterograde memory impairment in the others. Naming and problem solving deficits were found in a small number of cases. Only two patients were able to return to open employment. Severity of amnesia showed a significant relation with severity of damage to medical limbic system structures such as the hippocampus, with bilateral damage being particularly important. By contrast, there was a minimal relation between memory loss and severity of damage to the thalamus, to lateral temporal lobe areas, or to the frontal lobes.