CGRP， adrenomedullin (ADM)， and adrenomedullin 2 (ADM2) family peptides are important neuropeptides and hormones for the regulation of neurotransmission， vasotone， cardiovascular morphogenesis， vascular integrity， and feto?placental development. These peptides signal through CLR/RAMP1， 2 and 3 receptor complexes. CLR/RAMP1， or CGRP receptor， antagonists have been developed for the treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2， or ADM receptor， antagonists are being developed for the treatment of tumor growth/metastasis. Based on the finding that an acylated chimeric ADM/ADM2 analog potently stimulates CLR/RAMP1 and 2 signaling， we hypothesized that the binding domain of this analog could have potent inhibitory activity on CLR/RAMP receptors. Consistent with this hypothesis， we showed that acylated truncated ADM/ADM2 analogs of 27-31 residues exhibit potent antagonistic activity toward CLR/RAMP1 and 2. On the other hand， nonacylated analogs have minimal activity. Further truncation at the junctional region of these chimeric analogs led to the generation of CLR/RAMP1-selective antagonists. A 17-amino-acid analog (Antagonist 2-4) showed 100-fold selectivity for CLR/RAMP1 and was >100-fold more potent than the classic CGRP receptor antagonist CGRP8-37. In addition， we showed (1) a lysine residue in the Antagonist 2-4 is important for enhancing the antagonistic activity， (2) an analog consisted of an ADM sequence motif and a 12-amino-acid binding domain of CGRP exhibits potent CLR/RAMP1-inhibitory activity， and (3) a chimeric analog consisted of a somatostatin analog and an ADM antagonist exhibits dual activities on somatostatin and CLR/RAMP receptors. Because the blockage of CLR/RAMP signaling prevents migraine pain and suppresses tumor growth/metastasis， further studies of these analogs， which presumably have better access to the tumor microenvironment and nerve endings at the trigeminal ganglion and synovial joints as compared to antibody-based therapies， may lead to the development of better anti-CGRP therapy and alternative antiangiogenesis therapy. Likewise， the use of bifunctional somatostatin-ADM antagonist analogs could be a promising strategy for the treatment of high-grade neuroendocrine tumors by targeting an antiangiogenesis agent to the neuroendocrine tumor microenvironment.