Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type.

A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.

2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity.

A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.

Novel 1,3-bis(aryloxy)propanes as leukotriene D4 antagonists.

The synthesis and structure-activity relationships of a number of 1,3-bis(aryloxy)propanes, which are in vivo antagonists of LTD4 in the guinea pig, are described. One of these compounds, 4 (Wy-44,329), was not only approximately equipotent with the standard 1 (FPL 55712) in the LTC4 (ID50 = 0.17 and 0.23 mg/kg iv, respectively) and LTD4 (ID50 = 0.11 and 0.15 mg/kg iv, respectively) challenge models but also possessed greater potency in the ovalbumin challenge model (ID50 = 0.47 mg/kg and 4.1 mg/kg iv, respectively) and a longer duration of action. This compound was a competitive LTD4 antagonist on guinea pig ileum (pA2 = 9.4) and possessed mediator release (rat PCA, ID50 = 0.26 mg/kg iv) and 5-lipoxygenase (IC50 = 32 microM vs. 5-HETE) inhibitory activities.

Agonist (ovulation induction) and post-coital contraceptive properties of [D-Ala6] and [D-Trp6]-LHRH series.

Seven derivatives of LH-RH, representing the [D-Ala6] or [D-Trp6] series, with or without a Fujino modification, were evaluated for ovulation-inducing (agonist and post-coital contraceptive activity in rats. Six of these analogues had a high degree of agonist and pregnancy-terminating potency. In general, several modifications can result in a particular series of composite molecules that possess a biologic potency greater than each of its predecessors; this correlation of structure with activity was more consistent in the [D-Ala6]-series than in the [D-Trp6]-series. The relationship between structural modifications, resistance to enzyme degradation (based on literature reports) and increased biologic potency is discussed.

Antagonism of luteinizing hormone release and of ovulation by an analog of the luteinizing hormone-releasing hormone.

Two varients of LH-RH, less than Glu-D-Phe-Trp-D-Ala-Leu-Arg-Pro-Gly-NH2 (I) and less than Glu-D-Phe-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-NHCH2CH3 (II), have been synthesized by solid-phase methods. Both peptides strongly inhibit the LH-RH induced secretion of LH in an in vitro assay; however, only I proved effective in preventing ovulation in the 4-day cycling rat.

Luteinizing hormone-releasing hormone. Antiovulatory activity of analogs substituted in positions 2 and 6.

Ten analogs of luteinizing hormone-releasing hormone (LH-RH) substituted in position 2 with D-amino acids and at 6 with either a D-amino acid or a nonasymmetric amino acid were synthesized by solid-phase methodology and assayed for antiovulatory activity. [D-Phe2]-LH-RH substituted in the 6 position with D-Ala, D-Leu, D-Arg, D-(Ph)Gly, D-Phe, or 2-Me-Ala possessed varying degrees of antiovulatory activity. [D-p-F-Phe2-D-Ala6]-LH-RH was one of the most active antiovulatory compounds, while the [D-p-Cl-Phe2-D-Ala6]-LH-RH analog was devoid of activity at a comparable dose.