Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.

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Chronic haloperidol treatment during prenatal and postnatal development was found to induce long-term behavioral and psychopharmacological effects. Rats tested shortly after termination of the chronic treatment at weaning or as young adults were hyperactive in the open field and exhibited an attenuated behavioral response to amphetamine and an accentuated cataleptic response to later doses of haloperidol, when compared with control offspring of the same age. Tests at an intermediate interval (adolescence period) showed no significant difference from control offspring on any of these behavioral measures. Adult rats administered haloperidol chronically for the same duration were also hyperactive after termination of treatment. In contrast to the effects of haloperidol during development, these adults exhibited an accentuated behavioral response to amphetamine and an attenuated cataleptic response to a later dose of haloperidol. Compensatory mechanisms in response to chronic haloperidol treatment during development thus appear to be different from those in adulthood.

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We have studied three low molecular weight phosphoproteins, ARPP-16, ARPP-19, and ARPP-21 (cAMPregulated phosphoproteins of Mr 16,000, 19,000, and 21,000, respectively) in reaggregate cultures from various regions of fetal mouse brain. ARPP-16 and ARPP-21 were detected only in striatal and cortical cultures. In contrast, ARPP-19, which is structurally related to ARPP-16, was also present in reaggregate cultures prepared from thalamus and ventral and dorsal mesencephalon, as well as in monolayer cultures of astroglial cells. In striatal aggregates cultured over a 3-week period, the relative levels of ARPP-16, ARPP-21, and synapsin I/protein HIa (synaptic vesicle-associated phosphoproteins closely related to each other and treated as a single entity in the present study) increased with time, whereas the level of ARPP-19 decreased. Incubation of striatal aggregates with 8-Br-cAMP, forskolin, or vasoactive intestinal peptide increased the phosphorylation of all these proteins. We conclude that the state of phosphorylation of two proteins enriched in specific neurons (ARPP-16 and ARPP-21) and two more widely distributed proteins (ARPP-19 and synapsin I/protein IIla) is regulated by cAMP and vasoactive intestinal peptide in striatal cells in culture. These phosphoproteins may therefore play a role in mediating some of the actions of vasoactive intestinal peptide in the caudate-putamen.