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P Seeman

Publications and source records attributed to P Seeman.

At least 19 recordsLinked to original sources
PubMed1979

Neuroleptic receptors: stereoselectivity for neuroleptic enantiomers.

In order to identify a pair of neuroleptic enantiomers with the highest stereoselective interaction with neuroleptic/dopamine receptors, the effects of eight pairs of neuroleptic enantiomers were tested on the specific binding of 3H-spiperone to crude homogenates of calf caudate nucleus. The ratios of the Ki values were: (+)-butaclamol/(-)-butaclamol = 3000; dexclamol/(-)-analogue = 151; (+)-isobutaclamol/(-)-isobutaclamol = 146; (-)-CTC/(+)-CTC= 109; (-)-centbutindole/(+)-centbutindole = 20; S(+)-octoclothepin/R(-)-octoclothepin = 11. Thus, the neuroleptic receptor is highly stereoselective for the rigid butaclamol derivatives, but much less so for the flexible neuroleptics. The 3H-apomorphine binding site, however, had a stereoselectivity ratio of only 7 for isobutaclamol, further suggesting that the high affinity sites (i.e. nM) for 3H-neuroleptic binding and for 3H-apomorphine binding are different.

Animals↗
PubMed1979

Selective labeling of apomorphine receptors by 3H-LSD.

There are at least two types of dopamine receptors: the 3H-dopamine or 3H-apomorphine receptor (with high or nM affinity for dopamine), and the 3H-neuroleptic receptor (with low or microM affinity for dopamine). While 3H-LSD can label the 3H-neuroleptic receptor, this study was done in order to label the 3H-apomorphine/dopamine receptor site. In the presence of excess phentolamine, serotonin and spiperone (to preclude binding to alpha-adrenergic, serotonergic and neuroleptic receptors, respectively) similar concentrations of dopaminergic drugs inhibited the binding (to calf caudate) of 3H-LSD and 3H-apomorphine. This is compatible with the concept that the 3H-apomorphine/dopamine receptor and the 3H-neuroleptic/dopamine receptor are separate.

Animals↗
PubMed1979

Similar binding of 3H-ADTN and 3H-apomorphine to calf brain dopamine receptors.

The binding of 3H(+/-)-ADTN (of high specific activity; 7.6 Ci/mmole) to homogenates of calf striatum was investigated. The dissociation constant (KD) for the specific, saturable binding of 3H-(+/-)-ADTN was 1 nM and the density of specific sites was 100 fmoles/mg protein. The IC50 values (nM concentrations inhibiting specific binding by 50%) were 0.9 for (+/-)-N-propyl-norapomorphine, 3.0 for dopamine, 7 for (--)-adrenaline, 60 for (--)-noradrenaline and 4000 for isoproterenol, a series of potencies compatible with properties for a dopaminergic site. The (+)-enantiomer of ADTN was 10 times more potent than (--)-ADTN in competing for 3H-(+/-)-ADTN, while the (--)-enantiomer of 5-OH-dipropyl-ATN was 40 times more potent than the (+)-isomer. The IC50 values for various agonists against 3H-(+/-)-ADTN were similar to those against 3H-apomorphine or 3H-dopamine in the calf striatum. A comparison of these 3H-(+/-)-ADTN data to those for 3H-spiperone suggests that the two 3H-ligands label different receptor sites.

Animals↗
PubMed1979

Presynaptic subsensitivity as a possible basis for sensitization by long-term dopamine mimetics.

A possible cellular basis for dopaminergic sensitization by long-term dopamine mimetics was examined in rat brain striatum. Long-term apomorphine or amphetamine administration (10 mg/kg/day for 14 days) resulted in a decrease in the specific binding of 3H-apomorphine, but no change in 3H-haloperidol binding. Long-term apomorphine treatment also enhanced the cataleptogenic action of haloperidol, with many rats being spontaneously cataleptic after apomorphine withdrawal. It is suggested that the reduced 3H-apomorphine binding signifies less presynaptic receptors. This permits less autoregulation and enhanced dopamine agonist action, possibly accounting for the dopaminergic sensitization by long-term agonists.

Amphetamine↗
PubMed1978

Dopaminergic supersensitivity after neuroleptics: time-course and specificity.

It is known that a single dose of a neuroleptic can elicit dopaminergic supersensitivity in animals. On the other hand, the clinical syndrome of tardive dyskinesia takes many months of years to develop. To resolve this apparent discrepancy, it is possible that subclinical or latent tardive dyskinesia is fully compensated in most patients taking neuroleptics. In others, where the tardive dyskinesia is full-blown and grossly apparent, the dopaminergic supersensitivity may be decompensated. Such compensatory and decompensatory phases have been proposed earlier by Hornykiewicz (1974), in the case of Parkinson's Disease. Dopaminergic supersensitivity persists for a period proportional to the lenght of the neuroleptic treatment. It is not yet clear whether the relation between the length of treatment and the persistence of supersensitivity holds for very long treatments, but in principle the relationship might account for the persistence of tardive dyskinesia after years of neuroleptic pretreatment.

Animals↗
PubMed1978

Antiparkinsonian drug doses and neuroleptic receptors.

The clinical potency of 3 drugs, apomorphine, N-propylnorapomorphine, and bromocryptine, have been found to be closely correlated to their potencies in competing for 3H-haloperidol and 3H-spiroperidol both of which label the dopamine receptor. This correlation indicates that the direct binding assay may be used to predict clinical potencies of anti-parkinsonian drugs, and indicates that agonists as well as antagonists compete potently for 3H-neuroleptic binding.

Animals↗
PubMed1978

High-affinity 3H-serotonin binding to caudate: inhibition by hallucinogens and serotoninergic drugs.

The specific binding of 3H-serotonin to calf caudate homogenate was studied. The dissociation constant was 2nM and the number of specific sites was 14fmoles/mg protein. Of many drugs tested, inhibition of specific 3H-serotonin binding occurred almost exclusively with serotonin agonists and antagonists. The concentrations for 50% inhibition of 3H-serotonin binding by serotonergic agonists follow: bufotenin, 6nM; 5-methoxytryptamine, 12 nM; psilocin, 35nM; dimethyltryptamine, 220 nM; and tryptamine, 270 nM. The concentrations for the antagonists were: LSD 9.5 nM; methysergide 16nM and metergoline 25nM.

Animals↗