Olfactory sensory axons expressing a dominant-negative semaphorin receptor enter the CNS early and overshoot their target.

Sensory axons extend from the chick olfactory epithelium to the telencephalon well before the maturation of their target, the olfactory bulb. During a waiting period of several days, olfactory axons arrive and accumulate outside the CNS while the bulb differentiates beneath them. Semephorin-3A is expressed in the tel-encephalon during this period and has been proposed to prevent their entry into the CNS. We show that the misexpression of a dominant-negative neuropilin-1 that blocks SEMA-3A-mediated signaling in olfactory sensory axons induces many of them to enter the tel-encephalon prematurely and to overshoot the olfactory bulb. These results suggest that chemorepellents can prevent the premature innervation of immature targets.

A dominant negative receptor for specific secreted semaphorins is generated by deleting an extracellular domain from neuropilin-1.

Neuropilins have recently been characterized as receptors for secreted semaphorins. Here, we report the generation of a dominant negative form of neuropilin-1 by the deletion of one of its extracellular domains. Expression of this variant in cultured primary sympathetic neurons blocks the paralysis of growth cone motility normally induced by SEMA-3A (collapsin-1, semaphorin III, semaphorin D) and SEMA-3C (collapsin-3, semaphorin E) but not that induced by SEMA-3F (semaphorin IV). A truncated form of neuropilin-1 that is missing its cytoplasmic domain fails to act as a dominant negative receptor component. These results suggest that neuropilin-1 is a necessary component of receptor complexes for some, but not all, secreted semaphorin family members. Overexpression of dominant negative neuropilins should provide a powerful new method of blocking the functions of secreted semaphorins.

Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and adrenergic alpha1 receptors.

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.

N-aryl-N'-benzylpiperazines as potential antipsychotic agents.

N1-(2-Alkoxyphenyl)piperazines additionally containing an N4-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) test predictive of clinical antipsychotic activity and in in vitro receptor-binding assays. Certain of the compounds display high affinity for the D2, 5-HT1A, and alpha 1-adrenergic receptors. Structures bearing acyclic amide, lactam, and imide functionalities display good biological activity, with a preference for the 1,3-disubstituted phenyl ring relative to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible position of hydantoin attachment was investigated (e.g., substitution at N1, N3, and C5). The hydantoin involving attachment to N1 (24) was found to have good biological activity, whereas those hydantoins with attachment to N3 or C5 (22, 23, and 25) were inactive. Several of the smaller acetylated derivatives (30 and 33) have fair in vivo activity, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the D2 receptor (65 nM) as well as excellent in vivo activity. Benzylamino compounds display (viz. 27 and 35-38) moderate CAR activity but have surprising receptor affinity, often greater than those of comparable structures bearing a carbonyl (36 vs 7). Benzyl and benzhydryl alcohol compounds 40-48 are more active than amino structures 27 and 35-38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and 5-HT1A receptor binding.

A family of molecules related to collapsin in the embryonic chick nervous system.

Signaling molecules with either attractive or repulsive effects on specific growth cones are likely to play a role in guiding axons to their appropriate targets. A chick brain glycoprotein, collapsin, has been shown to be a good candidate for a repulsive guidance cue. We report here the discovery of four new molecules related to collapsin in chick brains. All contain a semaphorin domain. One is structurally very similar to collapsin but is only 50% identical in its amino acid sequence. We have named it collapsin-2. The collapsin-related genes exhibit distinct but overlapping patterns of mRNA expression in the developing spinal cord and the developing visual system. This family of collapsin-related molecules could potentially act as repulsive cues toward specific neuronal populations.

LiCl uncouples signal transduction in morphine-induced supraspinal antinociception in mice.

1. The present study examined whether LiCl antagonism of morphine-induced antinociception in mice occurs at mu-opioid receptors. 2. The antinociceptive ED50 value of intracerebroventricular morphine was maximally increased compared to controls 18 hr after LiCl (10 mmol/kg, s.c.) and remained significantly less (P < 0.05) 7 and 14 days after once-daily LiCl treatment. 3. There was no significant difference in [3H]-[D-Ala2,N-MePhe4,Gly- ol5]enkephalin affinity or receptor density compared to controls (KD = 0.43 nM, Bmax = 54.8 +/- 9.3 pM). 4. These results suggest that LiCl's effect is not on mu-opioid receptors, but rather on some distal site.

Migration status, education and fertility in Puerto Rico, 1960.

PIP: Based on a 25% sample of legally married, spouse-present women derived from the 1960 Census of the Commonwealth of Puerto Rico, the study analyses the correlation between migration and fertility. Age and education served as control variables and were examined to determine whether selective migration existed. Nonmigrant residents of the San Juan Standard Metropolitan Statistical Area (SMSA) were compared with San Juan SMSA residents who had migrated from a nonmetropolitan area since 1955. Sample women were divided into 4 age groups--14-24, 25-34, 35-44 and 45 and over. Among those aged 14-24, migrant women displayed lower fertility at all levels of education than their nonmigrating counterparts. In the 25-34 age group, migrant wives again showed lower fertility at all educational levels except elementary. In the 35-44 group, migrants demonstrated higher fertility before the education variable was controlled. Median education was 6.4 for migrants and 6.2 for nonmigrants in both the elementary and college educational categories. Migrants in the 45 and over age group had higher fertility and 50% had completed no more than 3.8 years of school compared with 4.4 years among nonmigrants. Data concludes that migration from nonmetropolitan areas appears to be related to lower fertility when migration occurrs at an early age allowing the reproductive span to be spent mainly in an urban environment. 2 types of migration streams may exist: 1) younger, better educated migrants adopting smaller family size norms; 2) older, poorly educated migrants with large families reflecting traditional values.^ieng