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Biomedical subjects

H B Hartman

Publications and source records attributed to H B Hartman.

9 recordsLinked to original sources
PubMed1995

3-[[(Aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: antipsychotic profile of iloperidone (HP 873).

A series of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles was synthesized and evaluated as potential antipsychotic D2/5-HT2 antagonists. Most of these compounds showed potent antipsychotic-like activity in an apomorphine-induced climbing mouse paradigm, with many also showing preferential mesolimbic activity, as indicated by their weaker effects in an apomorphine-induced stereotypy model. In receptor binding assays, many displayed a moderate affinity for the D2 receptor coupled with a significantly greater affinity for the 5-HT2 receptor: a property that has been suggested as necessary for atypicality. From this series, compound 45, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (iloperidone, HP 873), was further evaluated in a battery of in vivo and in vitro assays. This compound showed a 300-fold greater potency in inhibition of climbing than in inhibition of stereotypy or induction of catalepsy, and when evaluated chronically in an electrophysiological model, 45 caused a depolarization blockade of dopamine neurons in the A10 area of the rat brain but not in the A9 area. Additionally, it showed positive activity in a social interaction paradigm, suggesting potential efficacy against asociality, a component of the negative symptoms of schizophrenia. In chronic ex vivo studies, 45, similar to clozapine, caused a down regulation of 5-HT2 receptors but had no effect on the number of D2 receptors. Compound 45 is currently undergoing clinical evaluation.

Animals↗
PubMed1994

Benzisoxazole- and benzisothiazole-3-carboxamides as potential atypical antipsychotic agents.

A series of benzisoxazole- and benzisothiazole-3-carboxamides has been prepared and tested for potential antipsychotic activity. In general, the compounds showed an affinity for dopamine D2 and serotonin 5HT2A and 5HT1A receptors. Several members of this series have demonstrated activity in animal models predictive of potential antipsychotic activity. In addition, compounds 18, 19, 22, 27, 28, 43, and 44 have also shown a potential for reduced EPS liability as suggested by the ratio of activity seen in mesolimbic-mediated vs nigrostriatal-mediated behavioral assays.

Animals↗
PubMed1994

Regeneration and molting effects on a proprioceptor organ in the Dungeness crab, Cancer magister.

Decapoda Crustacea molt in order to grow; some species, such as the Dungeness crab Cancer magister, achieve a very large size. Does sensory neuron hyperplasia in internal proprioceptors accompany this growth? To determine this, neurons in propodite-dactylopodite (PD) chordotonal organs were counted in first walking legs of juvenile (5th through 9th instar) and adult (10th through 13th instar) C. magister. We found that the PD organs of J5 crabs have about 56 neurons; the number increases to about 61 neurons in J6 crabs. Significant hyperplasia now occurs because an average of 79 neurons are found in the PD organs of J7 crabs. Little to no hyperplasia accompanies the several succeeding juvenile and adult molts (ca. 82-86 neurons are present). Because autotomized limbs are regenerated upon molting, we also examined how the number of PD organ neurons in regenerated legs compares with those of pristine legs. Newly regenerated legs (termed 1st stage regenerates) have fewer sensory neurons than do their contralateral pristine partners (65 vs 81); larger regenerated legs which have attained nearly normal size as a result of additional molts (2nd stage regenerates) still have fewer neurons than their pristine partners (69 vs 81). Additionally, in contrast to those of pristine walking legs, the elastic strand of PD organs from 1st stage regenerates in a misshapen sheet containing a cluster of small neurons with no obvious functional organization. Nonetheless, neurophysiological recordings indicate that all the receptor types typical for pristine legs (movement and position cells) are represented. The PD organs of 2nd stage regenerates differentiate to the shape and neuronal organization of pristine legs.

Animals↗
PubMed1993

Cardiovascular effects of chloroethylclonidine, an irreversible alpha 1B-adrenoceptor antagonist, in the unanesthetized rat: a pharmacological analysis in vivo and in vitro.

The role of vascular alpha 1B-adrenergic receptors in the regulation of arterial pressure (MAP) and heart rate (HR) was examined by assessing the effect of i.v. chloroethylclonidine (CEC; irreversible alpha 1B antagonist) in unanesthetized, normotensive Long-Evans rats. MAP, HR and the pressor response to i.v. phenylephrine (PE) were monitored for 24 hr after saline or CEC (15 mg/kg and 25 mg/kg) injection. Neither i.v. saline nor CEC affected MAP or HR throughout the course of the study, yet the PE response was maximally inhibited (> 75% at 15 min) by both doses of CEC. The PE response recovered by 2 hr at the 15-mg/kg dose but remained inhibited up to 4 hr at 25 mg/kg. At 24 hr, all cardiovascular parameters returned to control levels. CEC (100 microM, 30 min) produced irreversible blockade of norepinephrine-induced contractions in rat aortic rings; prazosin (10 nM) and sodium thiosulphate (1 mM, a reagent that inactivates aziridinium ions) reversed CEC's inhibitory effect. Precyclized CEC and its hydrolysis product beta-hydroxyethylclonidine (beta-HEC) poorly antagonized aortic alpha 1B-receptors. Ex vivo analysis of aortic rings from saline and CEC-treated rats showed that PE-induced contractions were shifted to the right and maximally depressed in a dose-dependent manner after 24 hr. These results suggest that 1) CEC produces long lasting blockade of alpha 1B-adrenoceptors in vitro and in vivo via formation of an aziridinium ion intermediate and 2) vascular alpha 1B-adrenoceptors are not coupled to the tonic physiological regulation of MAP in the rat.

Adrenergic alpha-Antagonists↗
PubMed1991

Cardiac adenylate cyclase activity, positive chronotropic and inotropic effects of forskolin analogs with either low, medium or high binding site affinity.

A series of in vitro studies were conducted examining the adenylate cyclase stimulation, positive chronotropic and inotropic effects of forskolin and nine analogs which exhibited a range of [3H]forskolin binding site affinities (K1) from 0.020 to 3.174 microM. A significant (P less than .001) linear correlation (r = 0.94) was found between binding site affinity and adenylate cyclase stimulation (EC50) for forskolin and the nine structural analogs. Adenylate cyclase activity was also significantly correlated with the positive chronotropic and inotropic effects of these substances on isolated guinea pig atria. Compounds with K1 values between 0.020 and 1.136 microM produced concentration-dependent increases in heart rate and contractile force in isolated spontaneous and electrically paced guinea pig atria, respectively. In contrast, an analog with a K1 of 3.174 microM caused significant (P less than .05) negative chronotropic and inotropic effects at concentrations above 10 microM. The optimal separation between positive inotropic and chronotropic activity was found with compounds displaying potent [3H]forskolin binding site affinity but moderate adenylate cyclase stimulation, i.e., K1 and EC50 values of approximately 0.05 to 0.10 and 3 microM, respectively. The results of this study show that the forskolin analog, P87-7692 [7-desacetyl-7-(O-propionyl)-hydroxyl amino-carbonyl-forskolin], has marked activity with a wide separation between positive inotropic (248 +/- 41%) and chronotropic effects (43 +/- 13%) at 6.2 microM and may serve as a prototype for a forskolin-based cardiotonic.

Adenylyl Cyclases↗